Exploring naphthyl derivatives as SARS-CoV papain-like protease (PLpro) inhibitors and its implications in COVID-19 drug discovery

Abstract

Novel coronavirus disease 2019 (COVID-19) emerges as a serious threat to public health globally. The rapid spreading of COVID-19, caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), proclaimed the multitude of applied research needed not only to save the human health but also for the environmental safety. As per the recent World Health Organization reports, the novel corona virus may never be wiped out completely from the world. In this connection, the inhibitors already designed against different targets of previous human coronavirus (HCoV) infections will be a great starting point for further optimization. Pinpointing biochemical events censorious to the HCoV lifecycle has provided two proteases: a papain-like protease (PLpro) and a 3C-like protease (3CLpro) enzyme essential for viral replication. In this study, naphthyl derivatives inhibiting PLpro enzyme were subjected to robust molecular modelling approaches to understand different structural fingerprints important for the inhibition. Here, we cover two main aspects such as (a) exploration of naphthyl derivatives by classification QSAR analyses to find important fingerprints that module the SARS-CoV PLpro inhibition and (b) implications of naphthyl derivatives against SARS-CoV-2 PLpro enzyme through detailed ligand–receptor interaction analysis. The modelling insights will help in the speedy design of potent broad spectrum PLpro inhibitors against infectious SARS-CoV and SARS-CoV-2 in the future. Graphical Abstract Supplementary Information The online version contains supplementary material available at(10.1007/s11030-021-10198-3) .

Inhibitors of SARS-CoV-2 PLpro

“…The naphthyl ring in GRL-0617 , a moiety crucial for its activity, packs in a tight hydrophobic pocket of PLpro ( Figures 4A,B ). The original SAR for naphthyl ring subsitutions was performed for SARS-CoV PLpro: both empirical and computational methods confirmed its replacements obliterate compound activity (with the 1-naphthyl being preferred over the 2-naphthyl) ( Ghosh et al, 2009 ; Amin et al, 2021 ; Welker et al, 2021 ). Notwithstanding its contribution to the binding affinity of GRL-0617 to PLpro, naphthyl groups come with many liabilities (outlined below), so it is not surprising that many groups have attempted to find more suitable and druglike isosteres.…”

Ligand-based quantitative structural assessments of SARS-CoV-2 3CLpro inhibitors: An analysis in light of structure-based multi-molecular modeling evidences

“…Our group has already performed several extensive studies on the previous SARS-CoV inhibitors [ 3 , [18] , [19] , [24] , [25] , [26] , [27] , [28] , [29] , [30] ]. In this study, we have reported the structural analysis of 69 diverse SARS-CoV-2 3CL pro inhibitors by the regression-based quantitative structure-activity relationship (QSAR) methodologies to identify the fundamental structural features having crucial effects on SARS-CoV-2 3CL pro inhibition.…”

Virtual Screening of FDA Approved Drugs Library to Identify a Potential Inhibitor against NS2B-NS3 Protease of Yellow Fever Virus

“…Olsalazine may have a good binding capacity to SARS-CoV-2 M pro based on a recent in silico screening study, however Olsalazine appears to lose contact with M pro catalytic site in molecular dynamics simulation [41]. The seventh best hit in Table 1 is the antifungal agent (Naftifine), it is a naphthyl-based drug with known capacity to inhibit SARS-CoV PL pro [42]. Finally, the eighth hit in Table 1 is the diuretic agent (Chlorothiazide) and it may have a good aff against SARS-CoV-2 PL pro according to an in silico study [43].…”