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Molecular modeling evaluation of the binding effect of five protease inhibitors to COVID-19 main protease.

ABSTRACT: Coronavirus disease 2019 (COVID-19) has caused more than 840,000 deaths as of 31 August 2020 in the whole world. The COVID-19 main protease (M^pro) has been validated as an attractive target for drug design. In this work, the binding mechanisms of five protease inhibitors (e.g., danoprevir, darunavir, ASC09, lopinavir and ritonavir) to COVID-19 M^pro were investigated. Based on the docking score, five protease inhibitors structures were selected for further evaluation. It is found that most of the selected drug molecules bind stably to the COVID-19 M^pro from the molecular dynamics simulation. Moreover, the MM/PBSA free energy calculations suggest that lopinavir with positive charge might be most active against COVID-19 M^pro.

SUBMITTER: Liu J

PROVIDER: S-EPMC7834164 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Molecular modeling evaluation of the binding effect of five protease inhibitors to COVID-19 main protease.

Liu Jian J Zhai You Y Liang Lijun L Zhu Danyan D Zhao Qingwei Q Qiu Yunqing Y

Chemical physics 20201211

Coronavirus disease 2019 (COVID-19) has caused more than 840,000 deaths as of 31 August 2020 in the whole world. The COVID-19 main protease (M<sup>pro</sup>) has been validated as an attractive target for drug design. In this work, the binding mechanisms of five protease inhibitors (e.g., danoprevir, darunavir, ASC09, lopinavir and ritonavir) to COVID-19 M<sup>pro</sup> were investigated. Based on the docking score, five protease inhibitors structures were selected for further evaluation. It is ...[more]

PMID: 33519023

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Project description:Coronavirus (covid-19) infection is considered to be deadliest ever pandemic experienced by the human being. It has very badly affected the socio-economic health of human and stuck the scientific community to think and rethink about its complete eradication. But due to no effective treatment or unavailability of vaccine the health professional could not show any significant improvement to control the pandemic. The situation needs newer molecule, vaccine or effective treatment to control covid-19 infection. Different target in viruses has been explored and proteases enzymes were found to be therapeutically effective target for the design of potential anti-covid-19 molecule as it plays the vital role in viral replication and assembly. Structure-based drug design was employed to discover the small molecule of anti-covid-19. Here we considered the small library of naturally occurring polyphenolic compounds and molecular docking, Molecular dynamics (MD) simulations, free binding energy calculation and in-silico ADME calculations to identify the newer HITs. Based upon their score the two molecules were identified as promising candidate. The docking scores were found to be -7.643 and -7.065 for the HIT1 and HIT-2 respectively. In MD simulations study the RMSD values were found to be 4.3 Å & 4.9 Å respectively. To validate these results MM-GBSA was performed and their binding free energies were computationally determined. The prime energy values of identified HITs (-13412.45 & -13441.8 kJ/mole) were found to be very close proximity to reference molecule (-13493.05 kJ/mole). Then in-silico ADME calculations were performed to calculate the drug likeliness identified HITs. BY considering all the values comparative to reference molecule and obtained in-silico pharmacokinetic properties of identified HITs we can suggest that HIT-1 and HIT-2 would be the most promising molecules that can inhibit the main protease enzyme of covid-19. These two molecules would become the potential drug candidate for the treatment of covid-19 infections.

Dataset Information

Molecular modeling evaluation of the binding effect of five protease inhibitors to COVID-19 main protease.

Publications

Molecular modeling evaluation of the binding effect of five protease inhibitors to COVID-19 main protease.

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