Structural Analysis of COVID-19 Main Protease and its Interaction with the Inhibitor N3

Abstract

<i>Here, we analyze the structural features of a ligand binding domain (LBD) in COVID-19 main protease (MP) followed by the interactions between the inhibitor N3 and MP-LBD residues through the molecular dynamics simulations. The time based changes in physical parameters that includes root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (RG), dihedral distributions, residue velocity, radial distribution function (RDF) and H-bonding signify the degrees of folding states in MP-N3 complex formed by the superimposed b-barrels and flexible a-helices. Sharp and flat RDF peaks observed for the atom pairs dictate the flexibility of MP-LBD residues during their interactions with N3. In spite of larger solvent accessibility of N3, it interacts strongly with the LBD residues resulting in H-bonding. Among the LBD residues, GLU166 is found to have the lowest residue velocity that offers the sharp RDF peaks for three H-bonding atom pairs nearly at 2 Å radial distance, whereas GLY143 has the highest value of residue velocity giving rise to a flat RDF peak for the MP-N3 atom pair. Furthermore, electrostatic and van der Waals interaction energies between N3 and MP-LBD residues are noted to have the negative values. All these parameters explain the binding nature of N3 like inhibitors to the substrate binding sites of COVID-19 main protease. These analysis are expected to be a possible route applicable in drug designing mechanism to restrict the viral replication and transcription of COVID-19.</i><i> </i>

Research on Covid-19 from Biophysical Perspective

“…PDB . The structural analysis as well as viral protein-drug interaction can be studied by the methods of computation as explained in the recent literatures (Lamichhane and Ghimire, 2020;Wu, et al, 2020;Muralidharan, et al, 2020;Al-Khafaji , et al, 2020;Mirza, et al, 2020). According to Lamichhane and Ghimire (2020), the structural analysis of nCoV main protease (MP) liganded with inhibitor N3 has been performed in terms of the physical parameters such as root mean square deviation, root mean square fluctuation, radius of gyration, residue velocity, dihedral angle distributions, radial distribution function (RDF) and H-bonding, and the interactions between MP residues in the ligand binding domain (LBD) and inhibitor N3 have been studied in terms of electrostatic and van der Waals energies by means of MD simulations.…”

“…To the time of writing this report (23 rd June, 2020), no actual drugs or vaccines has been prescribed so far by WHO for COVID-19 treatment. Several drugs or inhibitors of SARS-CoV-2 such as inhibitor N3 Lamichhane and Ghimire, 2020) remdecivir (Wang, et al, 2020) favipiravir (Cai, et al, 2020), arbidol (Dong, et al, 2020) and dexomethasone (Heidi Ledford, Nature News 2020)are still under preclinical or clinical practices. It is necessary to test the efficacy and safety of the drugs or vaccines before prescribing them for the general public to investigate the medicine which actually works against COVID-19.…”

“…Some research works have been reported from Nepal exploring the public health response (Shrestha, et al, 2020), public health implications (Asim, et al, 2020;Pun, et al, 2020), preventive measures and government preparation (Khadka, et al, 2020;, and impact on economy and education Acharya, et al, 2020). In addition, a research with particular focus on the structural analysis of COVID-19 main protease and its interaction with the inhibitor N3 has been performed by using the biophysical aspects of MD simulations (Lamichhane and Ghimire, 2020). Also, the filtering efficiency and effectiveness of face masks for preventing COVID-19 are explained recently by Neupane et al (2019Neupane et al ( , 2020.…”

“…Figure6: Radial distribution functions of the interacting atom pairs between N3 and MP-LBD residues that make H-bonds to each other except the atom pair: H31(N3)-HG1(CYS145) obtained from the equilibrating MD simulations of MP-N3 complex in the cellular environment(Lamichhane and Ghimire, 2020) …”