Designing bioisosteres from candidate inhibitors of SARS-CoV-2 RBD: multi-variant and pan-coronaviral inhibitory potential

• Grant number: 21/05153-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2021
• End date: August 31, 2022
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Kathia Maria Honorio
• Grantee: Camila Fonseca Amorim da Silva
• Host Institution: Escola de Artes, Ciências e Humanidades (EACH). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The quest for bioactive substances against targets on SARS-CoV-2 could aid potential antivirals for COVID-19. Among the strategies, receptor-binding domain (RBD) inhibitors on the viral Spike (S) could block its recognition by angiotensin-converting enzyme type II (ACE2) in cells. Such strategy in the onset of infection is relevant, because even though vaccines are under development and distribution, those who might still require treatment must be considered; additionally, emerging variants instigate the study of small molecules as RBD inhibitors, being worthy the discovery of broad-spectrum antivirals. Therefore, this project intends to sort candidate RBD inhibitors of SARS-CoV-2 and related CoVs through structural changes, aiming to optimize their physico-chemical properties and biological activity. The bioisosteres to be generated will have been derived from previously identified hits and will be subjected to ADMET analyses and comparative docking studies, followed by molecular dynamics simulations between RBDs and the most promising bioisosteres - expecting to anticipate anti-SARS-CoV-2 strategies if or when future CoVs arise. (AU)