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

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.

A Computer-Based Methodology to Design Non-Standard Peptides Potentially Able to Prevent HOX-PBX1-Associated Cancer Diseases

“…MD frames were clustered in 10 groups based on the RMSD matrix by using both protein backbone and sidechains and setting a frequency of 10 steps at which the frames were analysed. The centroid frames for the most abundant clusters were: frame 880 (representative for 63 frames), frame 70 (representative for 34 frames), frame 540 (representative for 28 frames), frame 360 (representative for 22 frames), and frame 270 (representative for 15 frames) [ 55 ].…”

A Rational Design of α-Helix-Shaped Peptides Employing the Hydrogen-Bond Surrogate Approach: A Modulation Strategy for Ras-RasGRF1 Interaction in Neuropsychiatric Disorders

“…Finally, PROPKA [95] was run under pH 7.0 to optimise hydroxyl groups and Asn, Gln, and His states. In this work, 69 MD simulations were performed using Desmond [91,[96][97][98][99], as follows: 1 MD simulation of 50 ns for the Ras-Sos complex, 1 MD simulation of 50 ns for the Ras-RasGRF1 complex, 2 MD simulations of 500 ns for Ras in complex with the WT RB3 peptide, 1 MD simulation of 500 ns for Ras in complex with the 3 10 -HBS RB3 peptide, 16 MD simulations of 100 ns for Ras complexed with the point-mutated 3 10 -HBS peptides, and 48 MD simulations of 100 ns for Ras in complex with the combinatorial 3 10 -HBS peptides. All the trajectories were computed by applying the same MD settings below described.…”

Rational approaches to discover SARS-CoV-2/ACE2 interaction inhibitors: Pharmacophore-based virtual screening, molecular docking, molecular dynamics and binding free energy studies

“…Such in silico approaches are more rational, cost-effective, and time-saving [18] . In this regard, many attempts have recently been made to design new drugs against SARS-CoV-2 infection using computational methods [9] , [19] , [20] , [21] , [22] , [23] . These approaches include pharmacophore-based virtual screening, molecular docking, and molecular dynamics (MD) simulation.…”