Identification of lead small molecules for the design and development of potent severe acute respiratory syndrome coronavirus 2 main protease inhibitors DOI Creative Commons
Elvis Awuni

Journal of Chemical Research, Год журнала: 2025, Номер 49(2)

Опубликована: Март 1, 2025

The repercussions of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are catastrophic, and world has yet to achieve full recovery. Several inhibitors targeting SARS-CoV-2 main protease experiencing diminished efficacy owing resistance-inducing mutations. current situation implies that quest find potent resilient drugs overcome resistance must be a continuous effort. Here, multiple receptor virtual screening molecular dynamics (MD) simulation techniques were employed identify novel binders from an integrated small-molecule database as leads for discovery, design, development antivirals immune protease. was initially screened separately against five structures with different substrate-binding site conformations using GOLD program, after which fitness score control compound used cutoff create shortlist potential hits in each case. Then, 21 compounds at intersection all shortlists selected hits. subjected MD simulations, identifying four capable remaining bound up 100 ns. Analysis mode binding interactions between revealed fit better into conserved subpockets than interact important amino acid residues. Conjointly, energy, toxicity analysis results further demonstrated promising augment fight resistance.

Язык: Английский

Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir DOI Creative Commons
Laura Krismer, Helge Schöppe, Stefanie Rauch

и другие.

npj Viruses, Год журнала: 2024, Номер 2(1)

Опубликована: Июнь 24, 2024

Abstract The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring ability efficiently spread among humans and become pandemic. Its high mortality rate of up 35% absence effective targeted therapies call for development antiviral drugs this pathogen. Since beginning SARS-CoV-2 pandemic, extensive research focused on identifying protease inhibitors treatment SARS-CoV-2. Our intention was therefore assess whether these are viable options combating MERS-CoV. To that end, we used previously established assays quantify inhibition SARS-CoV-2, main proteases. Nirmatrelvir inhibited several proteases, whereas ensitrelvir less broadly active. simulate nirmatrelvir’s clinical use against subsequent resistance development, applied a safe, surrogate virus-based system. Using virus, selected hallmark mutations SARS-CoV-2-M pro , such as T21I, M49L, S144A, E166A/K/V L167F. In current study, pool MERS-CoV-M mutants, characterized modelled steric effect catalytic site mutants S142G, S142R, S147Y A171S.

Язык: Английский

Процитировано

6
Ensitrelvir treatment-emergent amino acid substitutions in SARS-CoV-2 3CLpro detected in the SCORPIO-SR phase 3 trial DOI Creative Commons
Takeki Uehara, Hiroshi Yotsuyanagi, Norio Ohmagari

и другие.

Antiviral Research, Год журнала: 2025, Номер unknown, С. 106097 - 106097

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
M49L and other drug resistance mutations emerging in individuals after administration of ensitrelvir in Japanese clinical settings DOI Creative Commons
Akira Inoue, Takaya Ichikawa, Daiki Wada

и другие.

Antiviral Research, Год журнала: 2025, Номер 236, С. 106118 - 106118

Опубликована: Фев. 17, 2025

Язык: Английский

Процитировано

0
Identification of lead small molecules for the design and development of potent severe acute respiratory syndrome coronavirus 2 main protease inhibitors DOI Creative Commons
Elvis Awuni

Journal of Chemical Research, Год журнала: 2025, Номер 49(2)

Опубликована: Март 1, 2025

The repercussions of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are catastrophic, and world has yet to achieve full recovery. Several inhibitors targeting SARS-CoV-2 main protease experiencing diminished efficacy owing resistance-inducing mutations. current situation implies that quest find potent resilient drugs overcome resistance must be a continuous effort. Here, multiple receptor virtual screening molecular dynamics (MD) simulation techniques were employed identify novel binders from an integrated small-molecule database as leads for discovery, design, development antivirals immune protease. was initially screened separately against five structures with different substrate-binding site conformations using GOLD program, after which fitness score control compound used cutoff create shortlist potential hits in each case. Then, 21 compounds at intersection all shortlists selected hits. subjected MD simulations, identifying four capable remaining bound up 100 ns. Analysis mode binding interactions between revealed fit better into conserved subpockets than interact important amino acid residues. Conjointly, energy, toxicity analysis results further demonstrated promising augment fight resistance.

Язык: Английский

Процитировано

0