Lead Finder

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Lead Finder is a computational chemistry tool designed for modeling protein-ligand interactions. It is used for conducting molecular docking studies and quantitatively assessing ligand binding and biological activity. It offers free access to users in commercial, academic, or other settings.

About

The original docking algorithm integrated into Lead Finder can be tailored for either quick but less accurate virtual screening applications or slower but more in-depth analyses.^[1]

Lead Finder is used by computational and medicinal chemists for drug discovery, pharmacologists, and toxicologists involved in in silico assessment of ADMET properties. Additionally, it is used by biochemists and enzymologists working on modeling protein-ligand interactions, enzyme specificity, and rational enzyme design. Lead Finder's specialization in ligand docking and binding energy estimation is a result of its advanced docking algorithm and the precision with which it represents protein-ligand interactions.^[2]

Docking algorithm

From a mathematical perspective, ligand docking involves the modelling of a multidimensional surface that describes the free energy associated with protein-ligand binding. This surface can be highly complex, with ligands possessing as many as 15-20 degrees of freedom, such as freely rotatable bonds.

Lead Finder's approach combines the use of genetic algorithm search, local optimization techniques, and knowledge gathered during the search process.

Scoring function

The Lead Finder scoring function represents protein-ligand interactions more precisely. The scoring function's model considers various types of molecular interactions.

In this scoring function, individual energy contributions are carefully adjusted with empirically derived coefficients tailored to objectives. such as the prediction of binding energies, the ranking of energy for docked ligand poses, and the ordering of active and inactive compounds during virtual screening experiments. To achieve these goals, Lead Finder employs three types of scoring functions, based on the same set of energy contributions but with different sets of energy-scaling coefficients.^[3]

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,^[4] Glide SP,^[5] Glide XP,^[6] Gold,^[7][8][9] LigandFit,^[10] MolDock,^[11] Surflex.^[12]

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. Lead Finder predicted bond energy precisely (RMSD = 1.5 kcal/mol) in less than one second per compound, on average.

References