Microscopic Factors Modulating the Interactions Between the SARS-CoV-2 Main Protease and α−Ketoamide Inhibitors

Abstract

<p>We performed 10 ns scale molecular dynamics simulations of 6 SARS-Cov-2 main protease/􀀀ketoamide inhibitor complexes in aqueous solution, in the phase before the inhibitor covalently binds to the protease's catalytic cysteine, using a polarizable multi-scale molecular modeling approach. For each simulation, 100 Mpro/inhibitor snapshots</p><p>(about 4 800 atoms) were extracted along the last 2 ns simulation segments. They were post processed using a fully quantum mechanical O(N) approach to decompose the protease in sets of fragments from which we computed the mean local interaction energies between the inhibitors and the different pockets of the protease catalytic domain. Contrary to earlier results, our analysis shows that the protease pocket S2 to be a key anchoring site able to lock within the catalytic domain an alpha-ketoamide inhibitor even before covalent bonding to the protease catalytic cysteine occurs. To target that pocket our computations suggest to consider hydrophobic groups, like cyclo-propyl or cyclo-hexyl.</p>

Synthesis of N-[1-(2-Acetyl-4,5-dimethoxyphenyl)propan-2-yl]benzamide and Its Copper(II) Complex

“…In the 13 C NMR spectrum of the ligand, the signal for the carbonyl group of COPh is at 202.6 ppm, and that for the carbonyl group of COCH 3 is observed at 166.6 ppm. Comparing the 13 C NMR spectra with the 13 C NMR of the copper complex we found that a 1.4 ppm shift for COPh moiety and 0.83 ppm for the COCH 3 group can be observed. A 2.05 ppm shift to a strong field for the CH proton is observed, as well.…”

“…According to in silico calculations, spasmolytic activity was predicted for N- [1-(2-acetyl-4,5-dimethoxyphenyl)propan-2-yl]benzamide and its Cu(II) complex, which synthesis was performed. Structure of the compounds were characterized by IR, Raman, 1 H, and 13 C NMR spectroscopy methods. The spectral data pointed out the bonding of the ligand through two oxygen and nitrogen atoms in Cu(II) complex.…”

“…The Raman spectra of compounds (the stirred crystals placed in aluminium disc) were measured on a RAM II (Bruker Optics) with a focused laser beam of Nd:YAG laser (1064 nm) from 4000 to 100 cm -1 at resolution of 2 cm -1 with 25 scans. 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance DRX250 spectrometer at 250 MHz or Bruker Avance III HD 500 spectrometer (Bruker, Billerica, MA, USA) at 500MHz ( 1 H NMR) and 125 MHz ( 13 C NMR), respectively. Chemical shifts are given in relative ppm and were referenced to tetramethylsilane as an internal standard.…”

“…In the past two decades, coronaviruses have appeared on a large pandemic scale displayed by the appearance of the severe acute respiratory syndrome virus (SARS-CoV) followed by another type of coronavirus (MERS-CoV). α-Ketoamides were studied as SARS-CoV-2 and other types of coronavirus inhibitors and showed very good activity [11][12][13].…”