Assessing the Potential Contribution of In Silico Studies in Discovering Drug Candidates That Interact with Various SARS-CoV-2 Receptors

Abstract

The COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly in the search for drug candidates that interact with various SARS-CoV-2 receptors. These studies involve the use of computer simulations and computational algorithms to predict the potential interaction of drug candidates with target receptors. The primary receptors targeted by drug candidates include the RNA polymerase, main protease, spike protein, ACE2 receptor, and transmembrane protease serine 2 (TMPRSS2). In silico studies have identified several promising drug candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, and Camostat Mesylate, among others. The use of in silico studies offers several advantages, including the ability to screen a large number of drug candidates in a relatively short amount of time, thereby reducing the time and cost involved in traditional drug discovery methods. Additionally, in silico studies allow for the prediction of the binding affinity of the drug candidates to target receptors, providing insight into their potential efficacy. This study is aimed at assessing the useful contributions of the application of computational instruments in the discovery of receptors targeted in SARS-CoV-2. It further highlights some identified advantages and limitations of these studies, thereby revealing some complementary experimental validation to ensure the efficacy and safety of identified drug candidates.

Keywords: ACE2; SARS-CoV-2; TMPRSS2; antiviral activity; drug candidates; in silico studies; molecular docking; molecular dynamics simulations; receptor–ligand complex.

Figure 1

The cleaving of SARS-CoV-2 receptors, as adapted from a source: The viral spike protein of the new coronavirus SARS-CoV-2 uses the same cellular receptor (ACE2) as SARS-CoV and requires the cellular protease TMPRSS2 for its activation [25]. The image was created with BioRender.

Figure 2

Targeting SARS-CoV-2 receptor binding domain, as adapted from a source: SARS-CoV-2 causes a reduction in the expression of the ACE2 receptor, without affecting ACE, by interacting with the ACE2 receptor through the spike protein. This interaction facilitates the virus’s entry into cells and its replication, leading to severe lung damage. Potential therapeutic strategies include the development of a vaccine based on the SARS-CoV-2 spike protein, the use of a TMPRSS2 inhibitor to prevent spike protein activation, the blockade of the surface ACE2 receptor using anti-ACE2 antibodies or peptides, and the use of a soluble ACE2 form. The soluble ACE2 can compete with SARS-CoV-2 for binding, reducing viral entry into cells, and safeguarding lung tissue from injury due to its unique enzymatic function [32].

Figure 3

Redrawn schematic illustration of prevalent computational methods utilized for inhibition design of SARS-CoV-2 receptors (such as ACE2, TMPRSS2, S protein, and main protease) as adapted from source [47].