Protease targeted COVID-19 drug discovery and its challenges: Insight into viral main protease (Mpro) and papain-like protease (PLpro) inhibitors

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) brutally perils physical and mental health worldwide. Unavailability of effective anti-viral drug rendering global threat of COVID-19 caused by SARS-CoV-2. In this scenario, viral protease enzymes are crucial targets for drug discovery. This extensive study meticulously focused on two viral proteases such as main protease (Mpro) and papain-like protease (PLpro), those are essential for viral replication. This review provides a detail overview of the targets (Mpro and PLpro) from a structural and medicinal chemistry point of view, together with recently reported protease inhibitors. An insight into the challenges in the development of effective as well as drug like protease inhibitors is discussed. Peptidomimetic and/or covalent coronavirus protease inhibitors possessed potent and selective active site inhibition but compromised in pharmacokinetic parameters to be a drug/drug like molecule. Lead optimization of non-peptidomimetic and/or low molecular weight compounds may be a better option for oral delivery. A masterly combination of adequate pharmacokinetic properties with coronavirus protease activity as well as selectivity will provide potential drug candidates in future. This study is a part of our endeavors which surely dictates medicinal chemistry efforts to discover effective anti-viral agent for this devastating disease.

Keywords: COVID-19; Mpro; Non-covalent inhibitor; PLpro; SARS-CoV-2; Structure-activity relationship (SAR).

Graphical abstract

Fig. 1

Three-dimensional structures of (A) SARS-CoV Mpro (PDB: 3ATW), (B) SARS-CoV-2 Mpro (PDB: 6LU7), (C) SARS-CoV PLpro (PDB: 4OW0), (D) SARS-CoV-2 PLpro (PDB: 6WUU). The amino acids formed catalytic dyad for Mpro and catalytic triad for PLpro are also highlighted.

Fig. 2

SARS-CoV-2 (A) Mpro and (B) PLpro binding sites.

Fig. 3

Structure of SARS-CoV-2 Mpro inhibitors.

Fig. 4

(A) Binding modes of SARS-CoV-2 Mpro inhibitors (N3, GC-376, 13b, 11a and 11b) at the active site, (B) Interaction of GC-376 with the amino acid residues, (C) Binding modes of SARS-CoV-2 PLpro inhibitors (VIR250 and VIR251) at the active site, (D) Interaction of VIR250 with the amino acid residues at active site of SARS-CoV-2 PLpro.

Fig. 5

Structure of SARS-CoV-2 Mpro inhibitors namely Baicalin, Baicalein, Boceprevir, GC-376, calpain inhibitors II and XII.

Fig. 6

Structure of SARS-CoV-2 Mpro inhibitors (11r, 13a, 13b, 14b, 11a and 11b).

Fig. 7

Structure of SARS-CoV-2 PLpro inhibitors (VIR250 and VIR251) and naphthyl based SARS-CoV-2 PLpro inhibitors.

Fig. 8

(A) Radar plot of four prototype compounds N3, 13b, Disulfiram, Carmofur after calculating ADME data (http://www.swissadme.ch/) suggesting the drug-likeness. Pink area represents the optimal range of each property. LIPO = Lipophilicity, SIZE = Molecular weight, POLAR = Polarity, INSOLU = Solubility, INSATU = Saturation, FLEX = Flexibility; (B) Correlation of SARS-CoV-2 Mpro inhibitory activity with eleven molecular descriptors (N = 25); (C) The correlation matrix of the physic-chemical and structural properties along with SARS-CoV-2 Mpro pIC₅₀ (N = 25) at significant p-statics; (D) The correlation matrix of the ADME properties along with SARS-CoV-2 Mpro pIC₅₀ (N = 25) at significant p-statics.