Targeting Receptor Binding Domain and Cryptic Pocket of Spike glycoprotein from SARS-CoV-2 by biomolecular modeling

TL;DR

This study uses biomolecular modeling to identify potential inhibitors targeting the SARS-CoV-2 spike protein's receptor binding domain and cryptic pocket, aiming to develop new COVID-19 treatments.

Contribution

It introduces a virtual screening and docking approach to find novel compounds targeting key spike protein sites for inhibiting viral entry.

Findings

Identified compounds with strong binding affinity to spike protein sites.

Selected top candidate compounds with favorable binding free energies.

Proposed potential inhibitors for further drug development.

Abstract

SARS-CoV-2, the causative agent of the disease known as Covid-19, has so far reported around 3,435,000 cases of human infections, including more than 239,000 deaths in 187 countries, with no effective treatment currently available. For this reason, it is necessary to explore new approaches for the development of a drug capable of inhibiting the entry of the virus into the host cell. Therefore, this work includes the exploration of potential inhibitory compounds for the Spike protein of SARS-CoV-2 (PDB ID: 6VSB), which were obtained from The Patogen Box. Later, they were filtered through virtual screening and molecular docking techniques, thus obtaining a top of 1000 compounds, which were used against a binding site located in the Receptor Binding Domain (RBD) and a cryptic site located in the N-Terminal Domain (NTD), resulting in good pharmaceutical targets for the blocking the infection. From the top 1000, the best compound (TCMDC-124223) was selected for the binding site. It interacts with specific residues that intervene in the recognition and subsequent entry into the host cell, resulting in a more favorable binding free energy in comparison to the control compounds (Hesperidine and Emodine). In the same way, the compound TCMDC-133766 was selected for the cryptic site. These identified compounds are potential inhibitors that can be used for the development of new drugs that allow effective treatment for the disease.