Lead Finder software is a

computational chemistry Computational chemistry is a branch of chemistry that uses computer simulation to assist in solving chemical problems. It uses methods of theoretical chemistry, incorporated into computer programs, to calculate the structures and properties of m ...

application for modeling protein-ligand interactions. The software can be used in molecular docking studies, for the quantitative evaluation of ligand binding and

biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...

. For individual, non-commercial and academic users the software is free.

About

Lead Finder software is an integrated solution for simulating structure and

binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mol ...

of protein-ligand complexes. The software combines automatic processing of protein structures, extra precision protein-ligand docking and calculation of free energy of ligand binding. Original docking algorithm provides a fast rate of calculations, which can be easily adjusted from more rapid (for

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. Virtua ...

applications) to slightly more slow and robust, while unique scoring function implemented in Lead Finder provides unsurpassed accuracy of calculations. Lead Finder is intended to meet the requirements of computational and medicinal chemists involved in

drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by ...

, pharmacologists and toxicologists involved in the evaluation of ADMET properties in silico, and biochemists and enzymologists working on modeling protein-ligand interactions,

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

specificity and rational enzyme design. Efficiency of ligand docking and binding energy estimations achieved by Lead Finder are due to docking algorithm and extra precision representation of protein-ligand interactions.

Docking algorithm

From a mathematical point of view

ligand docking In the field of molecular modeling, docking is a method which predicts the preferred orientation of one molecule to a second when a ligand and a target are binding (molecular), bound to each other to form a stable supramolecular chemistry, complex ...

represents a search for

global minimum In mathematical analysis, the maxima and minima (the respective plurals of maximum and minimum) of a function, known collectively as extrema (the plural of extremum), are the largest and smallest value of the function, either within a given ran ...

on the multidimensional surface describing the free energy of protein-ligand binding. With ligands having up to 15-20 degrees of freedom (freely rotatable bonds) and complex nature of energy surface, global optimum search represents a generally unsolved scientific task. To tackle this computationally challenging problem, Lead Finder applies a unique approach combining

genetic algorithm In computer science and operations research, a genetic algorithm (GA) is a metaheuristic inspired by the process of natural selection that belongs to the larger class of evolutionary algorithms (EA). Genetic algorithms are commonly used to gene ...

search, local optimization procedures, and a smart exploitation of the knowledge generated during the search run. Rational combination of different optimization strategies makes Lead Finder efficient in terms of coarse sampling of ligand's phase space and refinement of promising solutions.

Scoring function

Extra precise representation of protein-ligand interactions implemented in Lead Finder scoring function is the second (in addition to docking algorithm) component of successful ligand docking. Lead Finder

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 ...

is based on a semi-empiric molecular mechanical functional, which explicitly accounts for different types of molecular interactions. Individual energy contributions are scaled with empiric coefficients to fit particular purposes: accurate binding energy predictions, correct energy-ranking of docked ligand poses, correct rank-ordering of active and inactive compounds during virtual screening experiments. For these reasons, three distinct types of scoring functions based on the same set of energy contributions but different sets of energy-scaling coefficients are used by Lead Finder.

Docking success rate

Docking success rate was benchmarked as a percentage of correctly docked ligands (for which top-scored pose was within 2 Å RMSD from the reference ligand coordinates) for a set of protein-ligand complexes extracted from PDB. A set of 407 protein-ligand complexes was used for current docking success rate measurements. This set of complexes was combined from test sets used in original benchmarking studies of such docking programs as: FlexX, Glide SP, Glide XP, Gold, LigandFit, MolDock, Surflex.

Accuracy of binding energy estimations

The ability of Lead Finder to estimate free energy of protein-ligand binding was benchmarked against the set of 330 diverse protein-ligand complexes, which is currently the most extensive benchmarking study of such kind. Lead Finder demonstrated unique precision of binding energy prediction (RMSD = 1.5 kcal/mol) combined with high speed of calculations (less than one second per compound on average).

References

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