Computational Modeling of the SARS-CoV-2 Main Protease Inhibition by the Covalent Binding of Prospective Drug Molecules

Abstract

We illustrate modern modeling tools applied in the computational design of drugs acting as covalent inhibitors of enzymes. We take the Main protease (M pro) from the SARS-CoV-2 virus as an important present-day representative. In this work, we construct a compound capable to block M pro , which is composed of fragments of antimalarial drugs and covalent inhibitors of cysteine proteases. To characterize the mechanism of its interaction with the enzyme, the algorithms based on force fields, including molecular mechanics (MM), molecular dynamics (MD) and molecular docking, as well as quantum-based approaches, including quantum chemistry and quantum mechanics/molecular mechanics (QM/MM) methods, should be applied. The use of supercomputers is indispensably important at least in the latter approach. Its application to enzymes assumes that energies and forces in the active sites are computed using methods of quantum chemistry, whereas the rest of protein matrix is described using conventional force fields. For the proposed compound, containing the benzoisothiazolone fragment and the substitute at the uracil ring, we show that it can form a stable covalently bound adduct with the target enzyme, and thus can be recommended for experimental trials.

Computational Modeling of the Interaction of Molecular Oxygen with the Flavin-dependent Enzyme RutA

“…Computer simulations of elementary steps of the oxidation reactions require application of various modeling tools, including construction of all-atom three-dimensional model systems, preliminary relaxation of geometry parameters with the help of large-scale classical molecular dynamics (MD) simulations, and application of the quantum-based methods to locate stationary points on the potential energy surfaces of different spin multiplicity to estimate transition energies between electronic states, and to scan energy profiles along properly selected reaction coordinates. Application of the quantum mechanics/molecular mechanics (QM/MM) theory is an essential step in these simulations, which require high-performance supercomputer facilities [21].…”