TY - JOUR

T1 - Computer Aided Structure-Based Drug Design of Novel SARS-CoV-2 Main Protease Inhibitors: Molecular Docking and Molecular Dynamics Study

AU - Kolybalov, Dmitry S.

AU - Kadtsyn, Evgenii D.

AU - Arkhipov, Sergey G.

N1 - This work was partially supported by the Ministry of Science and Higher Education of the Russian Federation within the governmental order for SRF SKIF Boreskov Institute of Catalysis (project FWUR-2024-0040) and the Ministry of Science and Higher Education of the Russian Federation in the implementation of the research program “Use of synchrotron radiation for virological research” within the framework of the Federal Scientific and Technical Program for the Development of Synchrotron and Neutron Research and Research Infrastructure for 2019–2027 (Agreement No. 075-15-2021-1355 (12 October 2021)).

PY - 2024/1

Y1 - 2024/1

N2 - Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) virus syndrome caused the recent outbreak of COVID-19 disease, the most significant challenge to public health for decades. Despite the successful development of vaccines and promising therapies, the development of novel drugs is still in the interests of scientific society. SARS-CoV-2 main protease Mpro is one of the key proteins for the lifecycle of the virus and is considered an intriguing target. We used a structure-based drug design approach as a part of the search of new inhibitors for SARS-CoV-2 Mpro and hence new potential drugs for treating COVID-19. Four structures of potential inhibitors of (4S)-2-(2-(1H-imidazol-5-yl)ethyl)-4-amino-2-(1,3-dihydroxypropyl)-3-hydroxy-5-(1H-imidazol-5-yl)pentanal (L1), (2R,4S)-2-((1H-imidazol-4-yl)methyl)-4-chloro-8-hydroxy-7-(hydroxymethyl)octanoic acid (L2), 1,9-dihydroxy-6-(hydroxymethyl)-6-(((1S)-1,7,7-trimethylbicyclo [2.2.1]heptan-2-yl)amino)nonan-4-one (L3), and 2,4,6-tris((4H-1,2,4-triazol-3-yl)amino)benzonitrile (L4) were modeled. Three-dimensional structures of ligand–protein complexes were modeled and their potential binding efficiency proved. Docking and molecular dynamic simulations were performed for these compounds. Detailed trajectory analysis of the ligands’ binding conformation was carried out. Binding free energies were estimated by the MM/PBSA approach. Results suggest a high potential efficiency of the studied inhibitors.

AB - Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) virus syndrome caused the recent outbreak of COVID-19 disease, the most significant challenge to public health for decades. Despite the successful development of vaccines and promising therapies, the development of novel drugs is still in the interests of scientific society. SARS-CoV-2 main protease Mpro is one of the key proteins for the lifecycle of the virus and is considered an intriguing target. We used a structure-based drug design approach as a part of the search of new inhibitors for SARS-CoV-2 Mpro and hence new potential drugs for treating COVID-19. Four structures of potential inhibitors of (4S)-2-(2-(1H-imidazol-5-yl)ethyl)-4-amino-2-(1,3-dihydroxypropyl)-3-hydroxy-5-(1H-imidazol-5-yl)pentanal (L1), (2R,4S)-2-((1H-imidazol-4-yl)methyl)-4-chloro-8-hydroxy-7-(hydroxymethyl)octanoic acid (L2), 1,9-dihydroxy-6-(hydroxymethyl)-6-(((1S)-1,7,7-trimethylbicyclo [2.2.1]heptan-2-yl)amino)nonan-4-one (L3), and 2,4,6-tris((4H-1,2,4-triazol-3-yl)amino)benzonitrile (L4) were modeled. Three-dimensional structures of ligand–protein complexes were modeled and their potential binding efficiency proved. Docking and molecular dynamic simulations were performed for these compounds. Detailed trajectory analysis of the ligands’ binding conformation was carried out. Binding free energies were estimated by the MM/PBSA approach. Results suggest a high potential efficiency of the studied inhibitors.

KW - Mpro

KW - SARS-CoV-2

KW - SBDD

KW - gromacs

KW - structure-based drug design

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85183093841&origin=inward&txGid=5a99ba6a6f1a13dd00b60a716bbdfece

UR - https://www.mendeley.com/catalogue/3b593966-0bf3-3f49-817e-951efada2a9d/

U2 - 10.3390/computation12010018

DO - 10.3390/computation12010018

M3 - Article

VL - 12

JO - Computation

JF - Computation

SN - 2079-3197

IS - 1

M1 - 18

ER -