TY - JOUR
T1 - Discovering potent inhibitors against the Mpro of the SARS-CoV-2. A medicinal chemistry approach
AU - Mehmood, Aamir
AU - Nawab, Sadia
AU - Wang, Yanjing
AU - Chandra Kaushik, Aman
AU - Wei, Dong Qing
N1 - Publisher Copyright:
© 2022
PY - 2022/4/1
Y1 - 2022/4/1
N2 - The global pandemic caused by a single-stranded RNA (ssRNA) virus known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still at its peak, with new cases being reported daily. Although the vaccines have been administered on a massive scale, the frequent mutations in the viral gene and resilience of the future strains could be more problematic. Therefore, new compounds are always needed to be available for therapeutic approaches. We carried out the present study to discover potential drug compounds against the SARS-CoV-2 main protease (Mpro). A total of 16,000 drug-like small molecules from the ChemBridge database were virtually screened to obtain the top hits. As a result, 1032 hits were selected based on their docking scores. Next, these structures were prepared for molecular docking, and each small molecule was docked into the active site of the Mpro. Only compounds with solid interactions with the active site residues and the highest docking score were subjected to molecular dynamics (MD) simulation. The post-simulation analyses were carried out using the in-built GROMACS tools to gauge the stability, flexibility, and compactness. Principal component analysis (PCA) and hydrogen bonding were also calculated to observe trends and affinity of the drugs towards the target. Among the five top compounds, C1, C3, and C6 revealed strong interaction with the target's active site and remained highly stable throughout the simulation. We believe the predicted compounds in this study could be potential inhibitors in the natural system and can be utilized in designing therapeutic strategies against the SARS-CoV-2.
AB - The global pandemic caused by a single-stranded RNA (ssRNA) virus known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still at its peak, with new cases being reported daily. Although the vaccines have been administered on a massive scale, the frequent mutations in the viral gene and resilience of the future strains could be more problematic. Therefore, new compounds are always needed to be available for therapeutic approaches. We carried out the present study to discover potential drug compounds against the SARS-CoV-2 main protease (Mpro). A total of 16,000 drug-like small molecules from the ChemBridge database were virtually screened to obtain the top hits. As a result, 1032 hits were selected based on their docking scores. Next, these structures were prepared for molecular docking, and each small molecule was docked into the active site of the Mpro. Only compounds with solid interactions with the active site residues and the highest docking score were subjected to molecular dynamics (MD) simulation. The post-simulation analyses were carried out using the in-built GROMACS tools to gauge the stability, flexibility, and compactness. Principal component analysis (PCA) and hydrogen bonding were also calculated to observe trends and affinity of the drugs towards the target. Among the five top compounds, C1, C3, and C6 revealed strong interaction with the target's active site and remained highly stable throughout the simulation. We believe the predicted compounds in this study could be potential inhibitors in the natural system and can be utilized in designing therapeutic strategies against the SARS-CoV-2.
KW - COVID-19
KW - MD Simulation
KW - Mpro
KW - Respiratory syndrome
KW - Virtual screening
UR - http://www.scopus.com/inward/record.url?scp=85123832880&partnerID=8YFLogxK
U2 - 10.1016/j.compbiomed.2022.105235
DO - 10.1016/j.compbiomed.2022.105235
M3 - Article
C2 - 35123137
AN - SCOPUS:85123832880
SN - 0010-4825
VL - 143
JO - Computers in Biology and Medicine
JF - Computers in Biology and Medicine
M1 - 105235
ER -