tetano
Editor, Senior Moderator
Saudi Pharm J
. 2022 Dec 16.
doi: 10.1016/j.jsps.2022.12.007. Online ahead of print.
Screening and Identification of Potential MERS-CoV papain-like protease (PLpro) Inhibitors; Steady-state kinetic and Molecular Dynamic Studies
Mohammed Ali Dahhas[SUP] 1 [/SUP], Hamad Alkahtani[SUP] 2 [/SUP], Ajamaluddin Malik[SUP] 3 [/SUP], Abdulrahman A Almehizia[SUP] 4 [/SUP], Ahmed H Bakheit[SUP] 2 [/SUP], Siddique Akber Ansar[SUP] 2 [/SUP], Abdullah S AlAbdulkarim[SUP] 1 [/SUP], Lamees S Alrasheed[SUP] 2 [/SUP], Mohammad A Alsenaidy[SUP] 1 [/SUP]
Affiliations
Abstract
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.
Keywords: 3CLpro, 3-Chymotrypsin -like Protease; ADMET, Absorption, distribution, metabolism, excretion and toxicity; CFR, Case fatality rate; DTT, Dithiothreitol; Drug Design; Drug Discovery; E. coli, Escherichia coli; EDTA, Ethylenediaminetetraacetic acid; HCoV-, Human Coronavirus; HIA, Human intestinal absorption; His-tag, Histidine tag; IPTG, Isopropyl b-D-1-thiogalactopyranoside; Inhibitors; Kan, Kanamicyn; LB, Luria–Bertani; MD, Molecular dynamic; MERS-CoV PLpro Inhibitors; MOE, Molecular Operating Environment; MPLpro, MERS papain-like protease; Molecular Docking; Molecular dynamic simulation; Ni-NTA, Nickel-nitrilotri; Nonstructural proteins; PLIF, Protein- ligand interaction fingerprint; Papain-like protease; Protease; RMSD, Root Mean Square Deviation; RMSF, Root Mean Square Fluctuation; pp1a, Polyprotein 1a; pp1b, Polyprotein 1b.
. 2022 Dec 16.
doi: 10.1016/j.jsps.2022.12.007. Online ahead of print.
Screening and Identification of Potential MERS-CoV papain-like protease (PLpro) Inhibitors; Steady-state kinetic and Molecular Dynamic Studies
Mohammed Ali Dahhas[SUP] 1 [/SUP], Hamad Alkahtani[SUP] 2 [/SUP], Ajamaluddin Malik[SUP] 3 [/SUP], Abdulrahman A Almehizia[SUP] 4 [/SUP], Ahmed H Bakheit[SUP] 2 [/SUP], Siddique Akber Ansar[SUP] 2 [/SUP], Abdullah S AlAbdulkarim[SUP] 1 [/SUP], Lamees S Alrasheed[SUP] 2 [/SUP], Mohammad A Alsenaidy[SUP] 1 [/SUP]
Affiliations
- PMID: 36540698
- PMCID: PMC9756750
- DOI: 10.1016/j.jsps.2022.12.007
Abstract
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.
Keywords: 3CLpro, 3-Chymotrypsin -like Protease; ADMET, Absorption, distribution, metabolism, excretion and toxicity; CFR, Case fatality rate; DTT, Dithiothreitol; Drug Design; Drug Discovery; E. coli, Escherichia coli; EDTA, Ethylenediaminetetraacetic acid; HCoV-, Human Coronavirus; HIA, Human intestinal absorption; His-tag, Histidine tag; IPTG, Isopropyl b-D-1-thiogalactopyranoside; Inhibitors; Kan, Kanamicyn; LB, Luria–Bertani; MD, Molecular dynamic; MERS-CoV PLpro Inhibitors; MOE, Molecular Operating Environment; MPLpro, MERS papain-like protease; Molecular Docking; Molecular dynamic simulation; Ni-NTA, Nickel-nitrilotri; Nonstructural proteins; PLIF, Protein- ligand interaction fingerprint; Papain-like protease; Protease; RMSD, Root Mean Square Deviation; RMSF, Root Mean Square Fluctuation; pp1a, Polyprotein 1a; pp1b, Polyprotein 1b.