Development of docking programs for Lomonosov supercomputer

Vladimir Sulimov; İvan Ilin; Danil Kutov; Alexey Sulimov

doi:10.18596/jotcsa.634130

Research Article

Development of docking programs for Lomonosov supercomputer

Year 2020, Volume: 7 Issue: 1, 259 - 276, 15.02.2020

Vladimir Sulimov , İvan Ilin Danil Kutov Alexey Sulimov

https://doi.org/10.18596/jotcsa.634130

Cited By: 11

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 We show that all simplifications restricting docking accuracy can be withdrawn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
LomonosovMoscow 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 so-called 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.

Keywords

drug design, binding energy, docking, global optimization, force field

Supporting Institution

Russian Science Foundation

Project Number

Agreement No. 15-11-00025-П

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