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.

Keywords: COVID-19; Dynamic simulation; Molecular docking; Naphthyl derivative; SARS-CoV PLpro; SARS-CoV-2.

Fig. 1

Schematic plot for SARS-CoV-2 genome (PLpro enzyme is highlighted in red color)

Fig. 2

Schematic representation of current work design

Fig. 3

Contribution plot of different fragments (present in at least 5 compounds) identified by using consensus (red), GBM (light green), kNN (dark green), RF (cyan), and SVM (purple) models. The numbers M and N are different, signify the number of compounds containing a fragment and the number of fragments present in the dataset, respectively as some compounds have several identical fragments and contributions of those fragments were calculated separately

Fig. 4

Naphthyl derivaties featuring head (cyan) and tail (purple) connected by a linker marked as red

Fig. 5

Importance of different fingerprints for the inhibition of SARS-CoV PLpro enzyme: Orientation of 1-napthyl group in interactions with P248, P249 as well as Y269 for the best active inhibitor 33 in PDB: 4OW0 (a); position of methyl substituent of inhibitor 53 in interaction with T302 and Y265 in PDB: 3MJ5 (b); position of unsubstituted phenyl moiety in the docking pose of inhibitor 22 (c); interaction of piperidine moiety in the linker part with the amino acids in PDB: 4OW0 (d); Importance of CONH fragment in H-bond interactions with the main chain of amino acids G164, Y269 in PDB: 4OW0 (e); interaction of amino group in the docking pose of inhibitor 77 with the amino acid D165 (f)

Fig. 6

Superimposition of docking poses of compounds 23, 27 and 32 (yellow) in PLpro SARS-CoV-2 (PDB: 6WUU, marine blue) in surface representation a and interactions with important amino acids in the binding site b

Fig. 7

(a–c) Detailed ligand receptor interactions for compounds 23 a, 27 b and 32 c in PLpro SARS-CoV-2 (PDB: 6WUU). (d–f) Molecular dynamics plots are showing RMSD d, RMSF e and Rg f of the backbone-atoms of the apoPLpro SARS-CoV2 and its complexes. In MDS plots, apo, prt-23, prt-27, and prt-32 are represented as red, green, black and blue lines, respectively [here, prt = PLpro]

Fig. 8

The requisite structural features has to be considered to design new molecules with improved activity