Supercomputer docking with a large number of degrees of freedom

Сулимов, А. В.; Kutov, Danil; Ilin, İvan; Zheltkov, Dmitry A.; Тыртышников, Е. Е.; Сулимов, В. Б.

doi:10.1080/1062936x.2019.1659412

Cited by 7 publications

(8 citation statements)

References 30 publications

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“…For instance, improved geometry of Hbonds between the benzamidine moiety of the ligand and the carboxylic group of Asp189 is observed for 1LQD complex -see Fig. 3 in (51).…”

Section: Pdb Idmentioning

confidence: 98%

See 1 more Smart Citation

Development of docking programs for Lomonosov supercomputer

Сулимов¹,

Ilin²,

Kutov³

et al. 2020

Journal of the Turkish Chemical Society Section A: Chemistry

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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 We show that all simplifications restricting docking accuracy can be withdrawn and this can be done on the basis of modern supercomputer facilities allowing to perform docking of one ligand using many thousand computing cores.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.

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“…For instance, improved geometry of Hbonds between the benzamidine moiety of the ligand and the carboxylic group of Asp189 is observed for 1LQD complex -see Fig. 3 in (51).…”

Section: Pdb Idmentioning

confidence: 98%

“…These Hbonds are less favorable when ligand poses close to the ligand crystallized pose are placed into the rigid protein without any adjustment of protein atoms. For instance, improved geometry of Hbonds between the benzamidine moiety of the ligand and the carboxylic group of Asp189 is observed for 1LQD complex -see Fig.3 in (51).…”

Section: Pdb Idmentioning

confidence: 98%

Development of docking programs for Lomonosov supercomputer

Сулимов¹,

Ilin²,

Kutov³

et al. 2020

Journal of the Turkish Chemical Society Section A: Chemistry

View full text Add to dashboard Cite

show abstract

“…Such investigations have shown that movements of some protein atoms in the docking process improves positioning accuracy of docking [93,94]. The effectiveness of the TT-docking algorithm makes it possible to dock by SOL-P flexible ligands, oligopeptides, with a large number of torsions (more than 15 − 20) [87]. Such flexible ligands cannot be docked usually by classical docking programs.…”

Section: Sol-pmentioning

confidence: 99%

Supercomputer Docking

2019

JSFI

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This review is based on the peer-reviewed research literature including the author's own publications devoted to supercomputer docking. The general view on docking and its role at the initial stage of the rational drug design is presented. Molecules of medicine compounds selectively bind to the active site of a protein, which is responsible for the disease progression, and stop it. Docking programs perform positioning of molecules (ligands) in the active site of the protein and estimate the protein-ligand binding energy. The larger this energy is, the less concentration of the respective compound should be used to observe the desired effect. Several classical docking programs are described in short. Examples of the adaptation of existing docking programs to supercomputing and using them for virtual screening of millions of ligands are presented. Two novel generalized docking programs specially designed for multi-core docking of a single ligand on a supercomputer are described shortly. These programs find a sufficiently wide spectrum of low energy minima of a protein-ligand complex in the frame of a given force field. The quasi-docking procedure using the generalized docking program is described. Quasi-docking allows to perform docking with quantum-chemical semiempirical methods. Finally a summary is made based on the materials presented.

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“…[2][3][4] Among in silico methods in drug discovery, molecular docking has been widely used during the last three decades. [4][5][6] In protein-molecule docking, the optimal position, orientation and conformation (pose) of the molecule within the binding site is assessed ("docking stage"), and an estimation of its binding energy calculated. High-throughput docking (HTD) allows the screening of large chemical libraries (from thousands to millions of molecules) to generate a hit-list enriched with potential binders, which will be then advanced for biochemical and biological evaluation.…”

Section: Introductionmentioning

confidence: 99%