Development of docking programs for Lomonosov supercomputer

Abstract

The initial step of the rational drug design pipeline extremely needs an increase in effectiveness. This can be done using molecular modeling: docking and molecular dynamics. Docking programs are popular now due to their simple idea, quickness and ease of use. Nevertheless accuracy of these programs still leaves much to be desired and discovery by chance and experimental screening still play an important role. Docking performs ligand positioning in the target protein and estimates the protein-ligand binding free energy. While in many cases positioning accuracy of docking is satisfactory, the accuracy of binding energy calculations is insufficient to perform the hit-to-lead optimization. The accuracy depends on many approximations which are built into the respective model. We show that all simplifications restricting docking accuracy can be withdrawn and this can be done on the basis of modern supercomputer facilities allowing to perform docking of one ligand using many thousand computing cores. We describe in short the SOL docking program which is used during years for virtual screening of large ligand databases using supercomputer resources of Lomonosov Moscow State University. SOL to some extent is organized similarly to popular docking programs and reflects their limitations and advantages. We present our supercomputer docking programs, FLM and SOL-P, developed over the past 5 years for Lomonosov supercomputer of Moscow State University. These programs are free of most important simplifications and their performance shows the road map of the docking accuracy improvement. Some results of their performance for very flexible ligand docking into the rigid protein and docking of flexible ligands into the protein with some moveable protein atoms are presented. The socalled quasi-docking approach combining a force field and quantum chemical methods is described and it is shown that best docking accuracy is reached with the PM7 method and the COSMO solvent model.

New Blood Coagulation Factor XIIa Inhibitors: Molecular Modeling, Synthesis, and Experimental Confirmation

“…Each atom was assigned to a certain type in accordance with the MMFF94 force field [36]. Then, using the Aplite program, the coordinates of the protein center were determined as an input file for the SOLGRID [23,24] module. We used the geometric center of the native ligand cocrystallized with the corresponding protein to determine the center of docking cube.…”

“…In this study, docking was carried out by the SOL program [23,24]. SOL uses a precalculated grid of potentials that describes the interactions of ligand atoms with a rigid protein.…”

“…In this study, using the methods of structure-oriented virtual screening with the SOL docking program [23,24] and the subsequent calculation of the enthalpy of protein-ligand binding by the PM7 quantum chemical semiempirical method [25] with the COSMO implicit solvent model [26] using the MOPAC program [27], thirteen compounds were identified as potential inhibitors of blood coagulation factor XIIa. Experimental in vitro testing confirmed micromolar activity for four of the thirteen selected compounds.…”

In Search of Non-covalent Inhibitors of SARS-CoV-2 Main Protease: Computer Aided Drug Design Using Docking and Quantum Chemistry

“…SOL [53,56] is a classic docking program with many features used in popular docking programs [57]. However, developing this program we tried to make as few model simplifications as possible and to take into account the most important effects determining the accuracy of docking.…”

“…We present here the results of virtual screening of a database containing more than 40 000 structures of low molecular weight ligands using our own SOL [53,56] docking program. For the ligands with best docking scores the binding enthalpy is calculated using the PM7 quantumchemical semiempirical method and the implicit COSMO solvent model.…”