Drug design, often referred to as rational drug design or simply
rational design
In chemical biology and biomolecular engineering, rational design (RD) is an umbrella term which invites the strategy of creating new molecules with a certain functionality, based upon the ability to predict how the molecule's structure (specific ...
, is the
inventive process of finding new
medications based on the knowledge of a
biological target
A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
.
The drug is most commonly an
organic small molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ...
that activates or inhibits the function of a
biomolecule such as a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
, which in turn results in a
therapeutic
A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis.
As a rule, each therapy has indications and contraindications. There are many different ...
benefit to the
patient
A patient is any recipient of health care services that are performed by healthcare professionals. The patient is most often ill or injured and in need of treatment by a physician, nurse, optometrist, dentist, veterinarian, or other hea ...
. In the most basic sense, drug design involves the design of molecules that are complementary in
shape
A shape or figure is a graphical representation of an object or its external boundary, outline, or external surface, as opposed to other properties such as color, texture, or material type.
A plane shape or plane figure is constrained to lie ...
and
charge
Charge or charged may refer to:
Arts, entertainment, and media Films
* '' Charge, Zero Emissions/Maximum Speed'', a 2011 documentary
Music
* ''Charge'' (David Ford album)
* ''Charge'' (Machel Montano album)
* ''Charge!!'', an album by The Aqu ...
to the biomolecular target with which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on
computer modeling
Computer simulation is the process of mathematical modelling, performed on a computer, which is designed to predict the behaviour of, or the outcome of, a real-world or physical system. The reliability of some mathematical models can be dete ...
techniques.
This type of modeling is sometimes referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design.
In addition to small molecules,
biopharmaceutical
A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, t ...
s including
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
s
and especially
therapeutic antibodies
Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAbs) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those c ...
are an increasingly important class of drugs and computational methods for improving the affinity, selectivity, and stability of these protein-based therapeutics have also been developed.
The phrase "drug design" is to some extent a
misnomer. A more accurate term is
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
design (i.e., design of a molecule that will bind tightly to its target).
Although design techniques for prediction of binding affinity are reasonably successful, there are many other properties, such as
bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...
,
metabolic half-life,
side effects
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
, etc., that first must be optimized before a ligand can become a safe and efficacious drug. These other characteristics are often difficult to predict with rational design techniques. Nevertheless, due to high attrition rates, especially during
clinical phases of
drug development
Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for re ...
, more attention is being focused early in the drug design process on selecting candidate drugs whose
physicochemical
Physical chemistry is the study of macroscopic and microscopic phenomena in chemical systems in terms of the principles, practices, and concepts of physics such as motion, energy, force, time, thermodynamics, quantum chemistry, statistical mecha ...
properties are predicted to result in fewer complications during development and hence more likely to lead to an approved, marketed drug.
Furthermore,
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...
experiments complemented with computation methods are increasingly used in early
drug discovery to select compounds with more favorable
ADME (absorption, distribution, metabolism, and excretion) and
toxicological
Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating expo ...
profiles.
Drug targets
A
biomolecular target
A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
(most commonly a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
or a
nucleic acid) is a key molecule involved in a particular
metabolic or
signaling pathway that is associated with a specific disease condition or
pathology
Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in ...
or to the
infectivity
In epidemiology, infectivity is the ability of a pathogen to establish an infection. More specifically, infectivity is a pathogen's capacity for horizontal transmission — that is, how frequently it spreads among hosts that are not in a parent ...
or survival of a
microbial pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
. Potential drug targets are not necessarily disease causing but must by definition be disease modifying.
In some cases,
small molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ...
s will be designed to enhance or inhibit the target function in the specific disease modifying pathway. Small molecules (for example receptor
agonists,
antagonists
An antagonist is a character in a story who is presented as the chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...
,
inverse agonists, or
modulators; enzyme
activators or
inhibitors; or ion channel
openers or
blockers) will be designed that are complementary to the
binding site
In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...
of target. Small molecules (drugs) can be designed so as not to affect any other important "off-target" molecules (often referred to as
antitarget
In pharmacology, an antitarget (or off-target) is a receptor, enzyme, or other biological target that, when affected by a drug, causes undesirable side-effects. During drug design and development, it is important for pharmaceutical companies to en ...
s) since drug interactions with off-target molecules may lead to undesirable
side effects
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
. Due to similarities in binding sites, closely related targets identified through
sequence homology have the highest chance of cross reactivity and hence highest side effect potential.
Most commonly, drugs are
organic small molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ...
s produced through chemical synthesis, but biopolymer-based drugs (also known as
biopharmaceutical
A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, t ...
s) produced through biological processes are becoming increasingly more common. In addition,
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
-based
gene silencing
Gene silencing is the regulation of gene expression in a cell to prevent the expression of a certain gene. Gene silencing can occur during either transcription or translation and is often used in research. In particular, methods used to silence ge ...
technologies may have therapeutic applications.
Rational drug discovery
In contrast to traditional methods of
drug discovery (known as
forward pharmacology), which rely on
trial-and-error
Trial and error is a fundamental method of problem-solving characterized by repeated, varied attempts which are continued until success, or until the practicer stops trying.
According to W.H. Thorpe, the term was devised by C. Lloyd Morgan (18 ...
testing of chemical substances on
cultured cells or
animal
Animals are multicellular, eukaryotic organisms in the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motilit ...
s, and matching the apparent effects to treatments, rational drug design (also called
reverse pharmacology
In the field of drug discovery, reverse pharmacology also known as target-based drug discovery (TDD), a hypothesis is first made that modulation of the activity of a specific protein target thought to be disease modifying will have beneficial t ...
) begins with a hypothesis that modulation of a specific biological target may have therapeutic value. In order for a biomolecule to be selected as a drug target, two essential pieces of information are required. The first is evidence that modulation of the target will be disease modifying. This knowledge may come from, for example, disease linkage studies that show an association between mutations in the biological target and certain disease states. The second is that the target is "
druggable". This means that it is capable of binding to a small molecule and that its activity can be modulated by the small molecule.
Once a suitable target has been identified, the target is normally
cloned
Cloning is the process of producing individual organisms with identical or virtually identical DNA, either by natural or artificial means. In nature, some organisms produce clones through asexual reproduction. In the field of biotechnology, ...
and
produced and
purified. The purified protein is then used to establish a
screening assay. In addition, the three-dimensional structure of the target may be determined.
The search for small molecules that bind to the target is begun by screening libraries of potential drug compounds. This may be done by using the screening assay (a "wet screen"). In addition, if the structure of the target is available, a
virtual screen may be performed of candidate drugs. Ideally the candidate drug compounds should be "
drug-like", that is they should possess properties that are predicted to lead to
oral bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100 ...
, adequate chemical and metabolic stability, and minimal toxic effects. Several methods are available to estimate druglikeness such as
Lipinski's Rule of Five
Lipinski's rule of five, also known as Pfizer's rule of five or simply the rule of five (RO5), is a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has chemical pro ...
and a range of scoring methods such as
lipophilic efficiency. Several methods for predicting drug metabolism have also been proposed in the scientific literature.
Due to the large number of drug properties that must be simultaneously optimized during the design process,
multi-objective optimization
Multi-objective optimization (also known as multi-objective programming, vector optimization, multicriteria optimization, multiattribute optimization or Pareto optimization) is an area of multiple criteria decision making that is concerned with ...
techniques are sometimes employed. Finally because of the limitations in the current methods for prediction of activity, drug design is still very much reliant on
serendipity and
bounded rationality.
Computer-aided drug design
The most fundamental goal in drug design is to predict whether a given molecule will bind to a target and if so how strongly.
Molecular mechanics
Molecular mechanics uses classical mechanics to model molecular systems. The Born–Oppenheimer approximation is assumed valid and the potential energy of all systems is calculated as a function of the nuclear coordinates using Force field (chemi ...
or
molecular dynamics
Molecular dynamics (MD) is a computer simulation method for analyzing the physical movements of atoms and molecules. The atoms and molecules are allowed to interact for a fixed period of time, giving a view of the dynamic "evolution" of t ...
is most often used to estimate the strength of the
intermolecular interaction
An intermolecular force (IMF) (or secondary force) is the force that mediates interaction between molecules, including the electromagnetic forces of attraction
or repulsion which act between atoms and other types of neighbouring particles, e.g. a ...
between the
small molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ...
and its biological target. These methods are also used to predict the
conformation of the small molecule and to model conformational changes in the target that may occur when the small molecule binds to it.
Semi-empirical
Empirical evidence for a proposition is evidence, i.e. what supports or counters this proposition, that is constituted by or accessible to sense experience or experimental procedure. Empirical evidence is of central importance to the sciences an ...
,
ab initio quantum chemistry methods
''Ab initio'' quantum chemistry methods are computational chemistry methods based on quantum chemistry. The term was first used in quantum chemistry by Robert Parr and coworkers, including David Craig in a semiempirical study on the excite ...
, or
density functional theory
Density-functional theory (DFT) is a computational quantum mechanical modelling method used in physics, chemistry and materials science to investigate the electronic structure (or nuclear structure) (principally the ground state) of many-body ...
are often used to provide optimized parameters for the molecular mechanics calculations and also provide an estimate of the electronic properties (electrostatic potential,
polarizability
Polarizability usually refers to the tendency of matter, when subjected to an electric field, to acquire an electric dipole moment in proportion to that applied field. It is a property of all matter, considering that matter is made up of elementar ...
, etc.) of the drug candidate that will influence binding affinity.
Molecular mechanics methods may also be used to provide semi-quantitative prediction of the binding affinity. Also, knowledge-based
scoring function
In decision theory, a scoring rule
provides a summary measure for the evaluation of probabilistic predictions or forecasts. It is applicable to tasks in which predictions assign probabilities to events, i.e. one issues a probability distribution ...
may be used to provide binding affinity estimates. These methods use
linear regression,
machine learning
Machine learning (ML) is a field of inquiry devoted to understanding and building methods that 'learn', that is, methods that leverage data to improve performance on some set of tasks. It is seen as a part of artificial intelligence.
Machine ...
,
neural net
Artificial neural networks (ANNs), usually simply called neural networks (NNs) or neural nets, are computing systems inspired by the biological neural networks that constitute animal brains.
An ANN is based on a collection of connected units ...
s or other statistical techniques to derive predictive binding affinity equations by fitting experimental affinities to computationally derived interaction energies between the small molecule and the target.
Ideally, the computational method will be able to predict affinity before a compound is synthesized and hence in theory only one compound needs to be synthesized, saving enormous time and cost. The reality is that present computational methods are imperfect and provide, at best, only qualitatively accurate estimates of affinity. In practice it still takes several iterations of design, synthesis, and testing before an optimal drug is discovered. Computational methods have accelerated discovery by reducing the number of iterations required and have often provided novel structures.
Drug design with the help of computers may be used at any of the following stages of drug discovery:
# hit identification using
virtual screening
Virtual screening (VS) is a computational technique used in drug discovery to search libraries of small molecules in order to identify those structures which are most likely to bind to a drug target, typically a protein receptor or enzyme.
Virt ...
(structure- or ligand-based design)
#
hit-to-lead optimization of affinity and selectivity (structure-based design,
QSAR, etc.)
#
lead optimization
Hit to lead (H2L) also known as lead generation is a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds. These lead compo ...
of other pharmaceutical properties while maintaining affinity
![wiki Clustering](https://upload.wikimedia.org/wikipedia/commons/5/54/Wiki_Clustering.png)
In order to overcome the insufficient prediction of binding affinity calculated by recent scoring functions, the protein-ligand interaction and compound 3D structure information are used for analysis. For structure-based drug design, several post-screening analyses focusing on protein-ligand interaction have been developed for improving enrichment and effectively mining potential candidates:
* Consensus scoring
** Selecting candidates by voting of multiple scoring functions
** May lose the relationship between protein-ligand structural information and scoring criterion
* Cluster analysis
** Represent and cluster candidates according to protein-ligand 3D information
** Needs meaningful representation of protein-ligand interactions.
Types
![Drug discovery cycle 2](https://upload.wikimedia.org/wikipedia/commons/f/f9/Drug_discovery_cycle_2.png)
There are two major types of drug design. The first is referred to as
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
-based drug design and the second, structure-based drug design.
Ligand-based
Ligand-based drug design (or indirect drug design) relies on knowledge of other molecules that bind to the biological target of interest. These other molecules may be used to derive a
pharmacophore
300px, An example of a pharmacophore model.
A pharmacophore is an abstract description of molecular features that are necessary for molecular recognition of a ligand by a biological macromolecule. IUPAC defines a pharmacophore to be "an ensemble o ...
model that defines the minimum necessary structural characteristics a molecule must possess in order to bind to the target.
In other words, a model of the biological target may be built based on the knowledge of what binds to it, and this model in turn may be used to design new molecular entities that interact with the target. Alternatively, a
quantitative structure-activity relationship
Quantitative may refer to:
* Quantitative research, scientific investigation of quantitative properties
* Quantitative analysis (disambiguation)
* Quantitative verse, a metrical system in poetry
* Statistics, also known as quantitative analysis ...
(QSAR), in which a correlation between calculated properties of molecules and their experimentally determined
biological activity, may be derived. These QSAR relationships in turn may be used to predict the activity of new analogs.
Structure-based
Structure-based drug design (or direct drug design) relies on knowledge of the
three dimensional structure of the biological target obtained through methods such as
x-ray crystallography
X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
or
NMR spectroscopy
Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a spectroscopic technique to observe local magnetic fields around atomic nuclei. The sample is placed in a magnetic fie ...
.
If an experimental structure of a target is not available, it may be possible to create a
homology model
Homology modeling, also known as comparative modeling of protein, refers to constructing an atomic-resolution model of the "''target''" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous pr ...
of the target based on the experimental structure of a related protein. Using the structure of the biological target, candidate drugs that are predicted to bind with high
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Par ...
and
selectivity
Selectivity may refer to:
Psychology and behaviour
* Choice, making a selection among options
* Discrimination, the ability to recognize differences
* Socioemotional selectivity theory, in social psychology
Engineering
* Selectivity (radio), a ...
to the target may be designed using interactive graphics and the intuition of a
medicinal chemist
Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and developme ...
. Alternatively various automated computational procedures may be used to suggest new drug candidates.
Current methods for structure-based drug design can be divided roughly into three main categories.
The first method is identification of new ligands for a given receptor by searching large databases of 3D structures of small molecules to find those fitting the binding pocket of the receptor using fast approximate
docking programs. This method is known as
virtual screening
Virtual screening (VS) is a computational technique used in drug discovery to search libraries of small molecules in order to identify those structures which are most likely to bind to a drug target, typically a protein receptor or enzyme.
Virt ...
. A second category is de novo design of new ligands. In this method, ligand molecules are built up within the constraints of the binding pocket by assembling small pieces in a stepwise manner. These pieces can be either individual atoms or molecular fragments. The key advantage of such a method is that novel structures, not contained in any database, can be suggested.
A third method is the optimization of known ligands by evaluating proposed analogs within the binding cavity.
Binding site identification
Binding site
In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...
identification is the first step in structure based design.
If the structure of the target or a sufficiently similar
homolog
In biology, homology is similarity due to shared ancestry between a pair of structures or genes in different taxa. A common example of homologous structures is the forelimbs of vertebrates, where the wings of bats and birds, the arms of prima ...
is determined in the presence of a bound ligand, then the ligand should be observable in the structure in which case location of the binding site is trivial. However, there may be unoccupied
allosteric binding sites that may be of interest. Furthermore, it may be that only
apoprotein (protein without ligand) structures are available and the reliable identification of unoccupied sites that have the potential to bind ligands with high affinity is non-trivial. In brief, binding site identification usually relies on identification of
concave
Concave or concavity may refer to:
Science and technology
* Concave lens
* Concave mirror
Mathematics
* Concave function, the negative of a convex function
* Concave polygon, a polygon which is not convex
* Concave set
* The concavity of a ...
surfaces on the protein that can accommodate drug sized molecules that also possess appropriate "hot spots" (
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, t ...
surfaces,
hydrogen bonding
In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...
sites, etc.) that drive ligand binding.
Scoring functions
Structure-based drug design attempts to use the structure of proteins as a basis for designing new ligands by applying the principles of
molecular recognition
The term molecular recognition refers to the specific interaction between two or more molecules through noncovalent bonding such as hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, π-π interactions, halogen ...
.
Selective high
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Par ...
binding to the target is generally desirable since it leads to more
efficacious drugs with fewer side effects. Thus, one of the most important principles for designing or obtaining potential new ligands is to predict the binding affinity of a certain ligand to its target (and known
antitarget
In pharmacology, an antitarget (or off-target) is a receptor, enzyme, or other biological target that, when affected by a drug, causes undesirable side-effects. During drug design and development, it is important for pharmaceutical companies to en ...
s) and use the predicted affinity as a criterion for selection.
One early general-purposed empirical scoring function to describe the binding energy of ligands to receptors was developed by Böhm.
This empirical scoring function took the form:
where:
* ΔG
0 – empirically derived offset that in part corresponds to the overall loss of translational and rotational entropy of the ligand upon binding.
* ΔG
hb – contribution from hydrogen bonding
* ΔG
ionic – contribution from ionic interactions
* ΔG
lip – contribution from lipophilic interactions where , A
lipo, is surface area of lipophilic contact between the ligand and receptor
* ΔG
rot – entropy penalty due to freezing a rotatable in the ligand bond upon binding
A more general thermodynamic "master" equation is as follows:
where:
* desolvation –
enthalpic
Enthalpy , a property of a thermodynamic system, is the sum of the system's internal energy and the product of its pressure and volume. It is a state function used in many measurements in chemical, biological, and physical systems at a constant p ...
penalty for removing the ligand from solvent
* motion –
entropic
Entropy is a scientific concept, as well as a measurable physical property, that is most commonly associated with a state of disorder, randomness, or uncertainty. The term and the concept are used in diverse fields, from classical thermodynam ...
penalty for reducing the degrees of freedom when a ligand binds to its receptor
* configuration – conformational strain energy required to put the ligand in its "active" conformation
* interaction – enthalpic gain for "resolvating" the ligand with its receptor
The basic idea is that the overall binding free energy can be decomposed into independent components that are known to be important for the binding process. Each component reflects a certain kind of free energy alteration during the binding process between a ligand and its target receptor. The Master Equation is the linear combination of these components. According to Gibbs free energy equation, the relation between dissociation equilibrium constant, K
d, and the components of free energy was built.
Various computational methods are used to estimate each of the components of the master equation. For example, the change in polar surface area upon ligand binding can be used to estimate the desolvation energy. The number of rotatable bonds frozen upon ligand binding is proportional to the motion term. The configurational or strain energy can be estimated using
molecular mechanics
Molecular mechanics uses classical mechanics to model molecular systems. The Born–Oppenheimer approximation is assumed valid and the potential energy of all systems is calculated as a function of the nuclear coordinates using Force field (chemi ...
calculations. Finally the interaction energy can be estimated using methods such as the change in non polar surface, statistically derived
potentials of mean force, the number of hydrogen bonds formed, etc. In practice, the components of the master equation are fit to experimental data using multiple linear regression. This can be done with a diverse training set including many types of ligands and receptors to produce a less accurate but more general "global" model or a more restricted set of ligands and receptors to produce a more accurate but less general "local" model.
Examples
A particular example of rational drug design involves the use of three-dimensional information about biomolecules obtained from such techniques as X-ray crystallography and NMR spectroscopy. Computer-aided drug design in particular becomes much more tractable when there is a high-resolution structure of a target protein bound to a potent ligand. This approach to drug discovery is sometimes referred to as structure-based drug design. The first unequivocal example of the application of
structure-based drug design leading to an approved drug is the carbonic anhydrase inhibitor
dorzolamide
Dorzolamide, sold under the brand name Trusopt among others, is a medication used to treat high pressure inside the eye, including in cases of glaucoma. It is used as an eye drop. Effects begin within three hours and last for at least eight hours ...
, which was approved in 1995.
Another important case study in rational drug design is
imatinib
Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral chemotherapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kin ...
, a
tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
inhibitor designed specifically for the ''bcr-abl'' fusion protein that is characteristic for
Philadelphia chromosome
The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...
-positive
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
s (
chronic myelogenous leukemia and occasionally
acute lymphocytic leukemia
Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruisin ...
). Imatinib is substantially different from previous drugs for
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, as most agents of
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
simply target rapidly dividing cells, not differentiating between cancer cells and other tissues.
Additional examples include:
* Many of the
atypical antipsychotic
The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilizers and ne ...
s
*
Cimetidine, the prototypical
H2-receptor antagonist from which the later members of the class were developed
* Selective
COX-2
Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene ...
inhibitor
NSAID
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
s
*
Enfuvirtide
Enfuvirtide ( INN) is an HIV fusion inhibitor, the first of a class of antiretroviral drugs used in combination therapy for the treatment of HIV-1 infection. It is marketed under the trade name Fuzeon (Roche).
Structural formula
Enfuvirtide i ...
, a peptide HIV entry inhibitor
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Nonbenzodiazepines
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep proble ...
like
zolpidem
Zolpidem, sold under the brand name Ambien, among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and behavior ...
and
zopiclone
Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine used to treat difficulty sleeping. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases t ...
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Raltegravir
Raltegravir, sold under the brand name Isentress, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential ex ...
, an
HIV integrase inhibitor
*
SSRIs (selective serotonin reuptake inhibitors), a class of
antidepressants
*
Zanamivir
Zanamivir is a medication used to treat and prevent influenza caused by influenza A and influenza B viruses. It is a neuraminidase inhibitor and was developed by the Australian biotech firm Biota Holdings. It was licensed to Glaxo in 1990 and ap ...
, an
antiviral drug
Case studies
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5-HT3 antagonists
*
Acetylcholine receptor agonists
*
Angiotensin receptor antagonists
*
Bcr-Abl tyrosine-kinase inhibitor
Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philadel ...
s
*
Cannabinoid receptor antagonists
*
CCR5 receptor antagonist
CCR5 receptor antagonists are a class of small molecules that antagonize the CCR5 receptor. The C-C motif chemokine receptor CCR5 is involved in the process by which HIV, the virus that causes AIDS, enters cells. Hence antagonists of this rec ...
s
*
Cyclooxygenase 2 inhibitors
*
Dipeptidyl peptidase-4 inhibitors
Inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors or gliptins) are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4). They can be used to treat diabetes mellitus type 2.
The first agent of the class – sit ...
*
HIV protease inhibitors
Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS and hepatitis C. These protease inhibitors prevent viral replicat ...
*
NK1 receptor antagonists
*
Non-nucleoside reverse transcriptase inhibitors
Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replicatio ...
*
Nucleoside and nucleotide reverse transcriptase inhibitors
*
PDE5 inhibitors
A phosphodiesterase type 5 inhibitor (PDE5 inhibitor) is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplyi ...
*
Proton pump inhibitors
Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump.
They are the most potent inhibitor ...
*
Renin inhibitors
Renin inhibitors are pharmaceutical drugs inhibiting the activity of renin that is responsible for hydrolyzing angiotensinogen to angiotensin I, which in turn reduces the formation of angiotensin II that facilitates blood pressure.
Renin inhib ...
*
Triptans
Triptans are a family of tryptamine-based medication, drugs used as abortive medication in the treatment of migraines and cluster headaches. This drug class was first commercially introduced in the 1990s. While effective at treating individual h ...
*
TRPV1 antagonists
*
c-Met inhibitors
Criticism
It has been argued that the highly rigid and focused nature of rational drug design suppresses serendipity in drug discovery.
See also
*
Bioisostere
In medicinal chemistry, bioisosteres are chemical substituents or groups with similar physical or chemical properties which produce broadly similar biological properties to another chemical compound. In drug design, the purpose of exchanging one bi ...
*
Bioinformatics
Bioinformatics () is an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex. As an interdisciplinary field of science, bioinformatics combi ...
*
Cheminformatics
*
Drug development
Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for re ...
*
Drug discovery
*
List of pharmaceutical companies
This listing is limited to those independent companies and subsidiaries notable enough to have their own articles in Wikipedia. Both going concerns and defunct firms are included, as well as firms that were part of the pharmaceutical industry ...
*
Medicinal chemistry
Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and developme ...
*
Molecular design software Molecular design software is notable software for molecular modeling, that provides special support for developing molecular models ''de novo''.
In contrast to the usual molecular modeling programs, such as for molecular dynamics and quantum chemi ...
*
Molecular modification
Molecular modification is chemical alteration of a known and previously characterized lead compound for the purpose of enhancing its usefulness as a drug. This could mean enhancing its specificity for a particular body target site, increasing its ...
*
Retrometabolic drug design In the field of drug discovery, retrometabolic drug design is a strategy for the design of safer drugs either using predictable metabolism to an inactive moiety or using targeted drug delivery approaches. The phrase retrometabolic drug design was ...
References
External links
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{{Medicinal chemistry
Design of experiments
Drug discovery
Medicinal chemistry