Binding of Inhibitors to the Monomeric and Dimeric SARS-CoV-2 Mpro

Abstract

SARS-CoV-2 rapidly infects millions of people worldwide since December 2019. There is still no effective treatment for the virus, resulting in the death of more than one million of patients. Inhibiting the activity of SARS-CoV-2 main protease (Mpro), 3C-like protease (3CLP), is able to block the viral replication and proliferation. Although the dimer was shown to be the biologically active form of the SARS-CoV-2 Mpro, in this context, our study has revealed that <i>in silico</i> screening for inhibitors of SARS-CoV-2 Mpro can be reliably done using the monomeric structure of the receptor. Docking and fast pulling of ligand (FPL) simulations for both monomeric and dimeric forms correlate well with the corresponding experimental binding affinity data of 30 compounds. In particular, the correlation coefficients between computational and experimental binding free energy of the monomeric SARS-CoV-2 Mpro are approximately similar to the dimeric target. Moreover, the correlation coefficient between the rupture forces to binding free energy are roughly the same. Furthermore, the correlation coefficient between calculated metrics of the monomeric and dimeric SARS-CoV-2 Mpro is R = 0.74. Our study results show that it is possible to speed up computer-aided drug design for SARS-CoV-2 Mpro by focusing on the monomeric form instead of the larger dimeric one.

501Y.V2 Spike Protein Resists the Antibody in Atomistic Simulations

“…The obtained rupture force and pulling work were shown in Table 1. In particular, the form of pulling force curve is in good consistent with the previous works, 24,[64][65][66] in which the pulling force is linearly increased to the maximum value, 𝐹 Max , then rapidly decreased to zero. The average of 𝐹 Max and 𝑊 was then calculated upon the population of the representative structures.…”

Computational Estimation of Potential Inhibitors from the Known Drugs against the Main Protease of SARS-CoV-2

“…The SARS-CoV-2 Mpro in monomeric form can be used as a target for CADD to prevent the function of SARS-CoV-2 Mpro [12,13,24]. Autodock Vina [45], an opensource docking package, is one of the most popular docking protocols to rapidly estimate the binding affinity and binding pose of the protein and ligand complex.…”

“…Previously, the fast pulling of ligand (FPL) simulations was shown to effectively and accurately estimate the relative binding affinities of small molecules against HIV-1 protease or CHK1 with an affordable CPU time consumption [22,23]. It is worthy to mention that the computational combination of molecular docking and the FPL approach was validated on available inhibitors of SARS-CoV-2 Mpro and showed good agreement between calculated binding free energies and experimental values [12,13,24]. In this study, the possible inhibitors of SARS-CoV-2…”

“…The highest binding affinity profiles were chosen as the best docking conformation. The docking grid was determined as 2.6 × 2.6 × 2.6 nm which is able to accommodate the whole targeted active site [12][13][14]24].…”

“…The last snapshot of NPT simulations was then applied as the starting conformation of the steered-MD (SMD) simulation [22]. , and z is the displacement of the ligand mass center from its initial position) [24,[41][42][43]. The work of external force is calculated according to the following equation:…”