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. 2020 Oct 19;15(20):1921-1931.
doi: 10.1002/cmdc.202000259. Epub 2020 Sep 4.

Targeting SARS-CoV-2 RBD Interface: a Supervised Computational Data-Driven Approach to Identify Potential Modulators

Maria Rita Gulotta  1   2 , Jessica Lombino  1   2 , Ugo Perricone  1 , Giada De Simone  1 , Nedra Mekni  1 , Maria De Rosa  1 , Patrizia Diana  2 , Alessandro Padova  1
Affiliations

Targeting SARS-CoV-2 RBD Interface: a Supervised Computational Data-Driven Approach to Identify Potential Modulators

Maria Rita Gulotta et al. ChemMedChem. .

Abstract

Coronavirus disease 2019 (COVID-19) has spread out as a pandemic threat affecting over 2 million people. The infectious process initiates via binding of SARS-CoV-2 Spike (S) glycoprotein to host angiotensin-converting enzyme 2 (ACE2). The interaction is mediated by the receptor-binding domain (RBD) of S glycoprotein, promoting host receptor recognition and binding to ACE2 peptidase domain (PD), thus representing a promising target for therapeutic intervention. Herein, we present a computational study aimed at identifying small molecules potentially able to target RBD. Although targeting PPI remains a challenge in drug discovery, our investigation highlights that interaction between SARS-CoV-2 RBD and ACE2 PD might be prone to small molecule modulation, due to the hydrophilic nature of the bi-molecular recognition process and the presence of druggable hot spots. The fundamental objective is to identify, and provide to the international scientific community, hit molecules potentially suitable to enter the drug discovery process, preclinical validation and development.

Keywords: COVID-19; docking; molecular dynamics; pharmacophore; protein-protein interactions.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
SARS‐CoV‐2 PDB structures superposition unveiling RBD dynamic behaviour. On the left, overlap of SARS‐CoV‐2 S trimers in closed (PDB 6VXX) and open state (PDB 6VYB); on the right, a close‐up: the light blue structure shows PDB 6VXX S protein, while the blue chain exhibits the open state of PDB 6VYB S protein. PDB 6VXX: green, violet and light blue chains in closed conformations; PDB 6VYB: yellow, pink and blue chains in open conformations.
Figure 2
Figure 2
Spike RBD‐ACE2 PD interactions according to three interface regions. PDB ID 6M0J – light blue chain is ACE2 PD, while orange chain is Spike RBD. On the left, N‐terminal region; in the middle, central region; on the right, C‐terminal region.
Figure 3
Figure 3
RBD N‐terminal binding region description. On the left, protein surface of N‐terminal region; in the middle, residues composing the cavity; on the right, an example of ligand binding pose at N‐terminal region.
Figure 4
Figure 4
Pharmacophore maps built on RBD N‐terminal region. On the left, 6M17 Pharmacophore map; in the middle, 6M0J Pharmacophore map; on the right, shared pharmacophore map. Red spheres are hydrogen‐bond acceptors, green spheres are hydrogen bond donors, green‐red sphere is both hydrogen‐bond donor and acceptor, red spike is a negative ionisable feature and dotted spheres are features marked as optional.
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