TY - JOUR

T1 - Prospects for the structure‒function evolution of SARS-CoV-2 main protease inhibitors

AU - Bulygin, Anatoliy A.

AU - Kuznetsov, Nikita A.

N1 - This research was supported by the Russian-State-funded project # 121031300041-4.

PY - 2025/9/15

Y1 - 2025/9/15

N2 - The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the third case of widespread coronavirus infection. Together with the other two viruses, the SARS-CoV-2 virus is highly pathogenic, and some strains have a mortality rate of more than 1%. Moreover, it has become clear that coronaviruses mutate quite often, which reduces the effectiveness of available vaccines and forces the regular creation of new ones. The main viral protease Mpro is a suitable target for direct-acting drugs. Currently, there is only one recommended anticoronavirus drug, nirmatrelvir, which, however, does not have all the properties necessary for widespread and effective use. Thus, the development of a highly selective and effective protease inhibitor that can be taken orally still remains relevant. In this work, we performed an in-depth literature review of Mpro inhibitor studies and conducted extensive molecular dynamics simulations of Mpro-inhibitor complexes with computational prediction of binding ability and ADME (absorption, distribution, metabolism and excretion) properties of new compounds. On the basis of the literature review we composed a set of criteria that a potent inhibitor must meet. Then we created a set of possible inhibitors and their parts, which presumably allows all the necessary properties, namely, high affinity for the viral enzyme, selectivity, bioavailability and solubility, to be achieved.

AB - The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the third case of widespread coronavirus infection. Together with the other two viruses, the SARS-CoV-2 virus is highly pathogenic, and some strains have a mortality rate of more than 1%. Moreover, it has become clear that coronaviruses mutate quite often, which reduces the effectiveness of available vaccines and forces the regular creation of new ones. The main viral protease Mpro is a suitable target for direct-acting drugs. Currently, there is only one recommended anticoronavirus drug, nirmatrelvir, which, however, does not have all the properties necessary for widespread and effective use. Thus, the development of a highly selective and effective protease inhibitor that can be taken orally still remains relevant. In this work, we performed an in-depth literature review of Mpro inhibitor studies and conducted extensive molecular dynamics simulations of Mpro-inhibitor complexes with computational prediction of binding ability and ADME (absorption, distribution, metabolism and excretion) properties of new compounds. On the basis of the literature review we composed a set of criteria that a potent inhibitor must meet. Then we created a set of possible inhibitors and their parts, which presumably allows all the necessary properties, namely, high affinity for the viral enzyme, selectivity, bioavailability and solubility, to be achieved.

KW - Inhibitor binding

KW - Main protease

KW - Molecular dynamics

KW - SARS-CoV-2

KW - Coronavirus 3C Proteases/antagonists & inhibitors

KW - COVID-19 Drug Treatment

KW - Antiviral Agents/chemistry

KW - Humans

KW - Proline

KW - Lactams

KW - Structure-Activity Relationship

KW - Leucine

KW - Protease Inhibitors/chemistry

KW - Molecular Dynamics Simulation

KW - COVID-19/virology

KW - SARS-CoV-2/enzymology

KW - Nitriles

UR - https://www.scopus.com/pages/publications/105016056114

UR - https://www.mendeley.com/catalogue/bf62b37f-867f-3713-8f8b-02724020c121/

U2 - 10.1007/s10822-025-00654-9

DO - 10.1007/s10822-025-00654-9

M3 - Review article

C2 - 40952530

VL - 39

SP - 78

JO - Journal of Computer-Aided Molecular Design

JF - Journal of Computer-Aided Molecular Design

SN - 0920-654X

IS - 1

M1 - 78

ER -