Screening and identification of potential MERS-CoV papain-like protease (PLpro) inhibitors; Steady-state kinetic and Molecular dynamic studies

• Huvudupphovsmän: Mohammed Ali Dahhas (Författare, medförfattare), Hamad M. Alkahtani (Författare, medförfattare), Ajamaluddin Malik (Författare, medförfattare), Abdulrahman A Almehizia (Författare, medförfattare), Ahmed H. Bakheit (Författare, medförfattare), Siddique Akber Ansar (Författare, medförfattare), Abdullah S. AlAbdulkarim (Författare, medförfattare), Lamees S.Alrasheed (Författare, medförfattare), Mohammad A. Alsenaidy (Författare, medförfattare)
• Materialtyp: Bok
• Publicerad: Elsevier, 2023-02-01T00:00:00Z.
• Ämnen: article
• Länkar: Connect to this object online.

Sammanfattning

MERS-CoV belongs to the coronavirus group. Recent years have seen a rash of coronavirus epidemics. In June 2012, MERS-CoV was discovered in the Kingdom of Saudi Arabia, with 2,591 MERSA cases confirmed by lab tests by the end of August 2022 and 894 deaths at a case-fatality ratio (CFR) of 34.5% documented worldwide. Saudi Arabia reported the majority of these cases, with 2,184 cases and 813 deaths (CFR: 37.2%), necessitating a thorough understanding of the molecular machinery of MERS-CoV. To develop antiviral medicines, illustrative investigation of the protein in coronavirus subunits are required to increase our understanding of the subject. In this study, recombinant expression and purification of MERS-CoV (PLpro), a primary goal for the development of 22 new inhibitors, were completed using a high throughput screening methodology that employed fragment-based libraries in conjunction with structure-based virtual screening. Compounds 2, 7, and 20, showed significant biological activity. Moreover, a docking analysis revealed that the three compounds had favorable binding mood and binding free energy. Molecular dynamic simulation demonstrated the stability of compound 2 (2-((Benzimidazol-2-yl) thio)-1-arylethan-1-ones) the strongest inhibitory activity against the PLpro enzyme. In addition, disubstitutions at the meta and para locations are the only substitutions that may boost the inhibitory action against PLpro. Compound 2 was chosen as a MERS-CoV PLpro inhibitor after passing absorption, distribution, metabolism, and excretion studies; however, further investigations are required.

Beskrivning

1319-0164
10.1016/j.jsps.2022.12.007