Lead–Finder: Solutions

Solutions

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Figure 1. PDB structure of tyrosine phosphatase (pdb id 1bzh) — the starting structure for ligand docking studies.

Figure 2. Tyrosine phosphatase structure prepared for ligand docking: Lead-Finder restored missing amino acids side chains (not resolved in the pdb structure), calculated ionization state of the protein and added hydrogen atoms accordingly.

Figure 3. Reference crystallographic position of tyrosine phosphatase inhibitor 3-(oxalyl-amino)-naphthalene-2-carboxylic acid from pdb structure 1c84.

Figure 4. Inhibitor position predicted by Lead-Finder (reference pdb structure 1c84). Electrostatic and hydrogen bonding interactions are presented by dot surface.
Calculated _ΔG_binding=-8.03_kcal/mol.
Experimental K_i=9.9μM

Figure 5. Ligand possition predicted by docking (reference pdb structure 1c86).
Calculated _ΔG_binding=-8.42_kcal/mol.
Experimental K_i=14.0μM

Figure 6. Ligand possition predicted by docking (reference pdb structure 1c85).
Calculated _ΔG_binding=-7.39_kcal/mol.
Experimental K_i=23.0μM

Figure 7. Ligand possition predicted by docking (reference pdb structure 1c88).
Calculated _ΔG_binding=-9.72_kcal/mol.
Experimental K_i=0.29μM

Figure 8. Binding of de novo
designed tyrosine phosphatase inhibitor predicted by Lead-Finder.
Calculated _ΔG_binding=-10.3_kcal/mol.

What tasks Lead-Finder can solve for you:

Lead-Finder combines extra precise protein-ligand docking and binding energy estimation with a high speed of calculations providing efficient solutions for the following tasks:

Protein structure preparation (cleaning)
Lead-Finder automatically prepares fully functional protein structures (for docking and other molecular modeling purposes) starting from crude heavy atom coordinates (usually present in PDB files and homology models) by adding hydrogen atoms to protein residues (ligands, substrates, cofactors) at a given pH. Original electrostatic model is implemented in Lead-Finder for accurate calculations of ionization properties of proteins, which was validated in predicting 100 diverse pKa values of ionizable protein residues.
Ligand docking
Lead-Finder correctly predicts the structure of non-covalent and covalently bound protein-ligand complexes. Accuracy of protein-ligand docking was validated on the set of 407 protein-ligand complexes, which is currently the most extensive benchmarking study of such kind. Our test set was composed of test sets of such docking programs as FlexX, Glide SP, Glide XP, Gold, LigandFit, MolDock, Surflex which allowed straightforward comparison of Lead-Finder and original results for the competitive programs. As can be seen from our benchmarking studies, Lead-Finder outperformed all competitive programs on their native test sets.
Virtual screening
Lead-Finder can screen massive libraries of chemical compounds against a protein target to find potent binders with high fidelity at a high speed of calculations (~5000 compounds per processor/core per day). Ability of Lead-Finder to find active compounds in mixtures with inactive was extensively validated on the set of 34 therapeutically relevant protein targets, showing impressive enrichment results in almost all cases.
Binding energy estimations
Lead-Finder performs extra precise estimations of the free energy of protein-ligand binding based on an original semi-empiric molecular-mechanical scoring function. Accuracy of binding energy estimations was validated on the set of experimentally measured binding energies of 330 diverse protein-ligand complexes, which is currently the most extensive benchmarking study of such kind. Root mean square deviation of Lead-Finder predictions from experimental binding energies comprised 1.50 kcal/mol, which is the highest accuracy compared to competitive docking programs.