SARS-CoV-2 Papain-Like Protease Potential Inhibitors-In Silico Quantitative Assessment.

Adam Stasiulewicz,Mai Lan Nguyen,Barbara Bełza,Alicja W Maksymiuk,Joanna I Sulkowska

doi:10.3390/ijms22083957

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for developing new antiviral drugs. In this study, we searched for novel, noncovalent potential PLpro inhibitors by employing a multistep in silico screening of a 15 million compound library. The selectivity of the best-scored compounds was evaluated by checking their binding affinity to the human ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which, as a deubiquitylating enzyme, exhibits structural and functional similarities to the PLpro. As a result, we identified 387 potential, selective PLpro inhibitors, from which we retrieved the 20 best compounds according to their IC50 values toward PLpro estimated by a multiple linear regression model. The selected candidates display potential activity against the protein with IC50 values in the nanomolar range from approximately 159 to 505 nM and mostly adopt a similar binding mode to the known, noncovalent SARS-CoV-2 PLpro inhibitors. We further propose the six most promising compounds for future in vitro evaluation. The results for the top potential PLpro inhibitors are deposited in the database prepared to facilitate research on anti-SARS-CoV-2 drugs.

Highlights

Due to the alarming spread levels and rising infection numbers, on 11 March 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) as a world health emergency and characterized it as a pandemic [1]
SARS-CoV-2 papain-like protease (PLpro) is a monomeric enzyme that may be divided into two main domains—the catalytic domain and the ubiquitin-like (Ubl) domain
Such methods require an extensive validation each time they are used for a new molecular target. We describe such validation in detail in the Methods section. As this is a crucial matter for such a type of an in silico project, in the few paragraphs, we highlight the results of the validation of methods we selected for each part of our procedure

Summary

Introduction

Due to the alarming spread levels and rising infection numbers, on 11 March 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) as a world health emergency and characterized it as a pandemic [1]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as pathogen causing COVID-19 [2]. People infected with SARS-CoV-2 can suffer from mild symptoms such as high fever, cough, and fatigue, but the virus can cause acute respiratory difficulties, multiple organ failure, and death. The elderly and people with comorbidities are especially at risk of a severe course of the disease [3]. As of March 2021, more than 2.5M people have died from COVID-19 and more than 114M confirmed infection cases have been reported around the world [4,5]. As the disease has a substantial impact on global health and significantly affects social and economic aspects, the scientific community has put great effort toward developing new treatments

Objectives

Methods

Results

Conclusion