Design and Identification of Inhibitors for the Spike-ACE2 Target of SARS-CoV-2

Abstract

settingsOrder Article Reprints Open AccessArticle Design and Identification of Inhibitors for the Spike-ACE2 Target of SARS-CoV-2 by Ruan S. Bastos 1,2,*,Lúcio R. de Lima 1,2,Moysés F. A. Neto 3,Maryam 4,Numan Yousaf 4ORCID,Jorddy N. Cruz 2ORCID,Joaquín M. Campos 5,6ORCID,Njogu M. Kimani 7ORCID,Ryan S. Ramos 2ORCID andCleydson B. R. Santos 1,2,*ORCID 1 Graduate Program in Medicinal Chemistry and Molecular Modeling, Federal University of Pará, Belem 66075-110, PA, Brazil 2 Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapa 68903-419, AP, Brazil 3 Laboratory of Molecular Modeling, State University of Feira de Santana, Feira de Santana 44036-900, BA, Brazil 4 Department of Biosciences, COMSATS University Islamabad, Park Road, Islamabad 45550, Pakistan 5 Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus of Cartuja, University of Granada, 18071 Granada, Spain 6 Biosanitary Institute of Granada (ibs.GRANADA), University of Granada, 18071 Granada, Spain 7 Department of Physical Sciences, University of Embu, Embu 6-60100, Kenya * Authors to whom correspondence should be addressed. Int. J. Mol. Sci. 2023, 24(10), 8814; https://doi.org/10.3390/ijms24108814 Received: 12 September 2022 / Revised: 23 November 2022 / Accepted: 28 November 2022 / Published: 16 May 2023 (This article belongs to the Special Issue The Research about Computer-Aided Drug Design) Download Browse Figures Versions Notes Abstract When an epidemic started in the Chinese city of Wuhan in December 2019, coronavirus was identified as the cause. Infection by the virus occurs through the interaction of viral S protein with the hosts’ angiotensin-converting enzyme 2. By leveraging resources such as the DrugBank database and bioinformatics techniques, ligands with potential activity against the SARS-CoV-2 spike protein were designed and identified in this investigation. The FTMap server and the Molegro software were used to determine the active site of the Spike-ACE2 protein’s crystal structure. Virtual screening was performed using a pharmacophore model obtained from antiparasitic drugs, obtaining 2000 molecules from molport®. The ADME/Tox profiles were used to identify the most promising compounds with desirable drug characteristics. The binding affinity investigation was then conducted with selected candidates. A molecular docking study showed five structures with better binding affinity than hydroxychloroquine. Ligand_003 showed a binding affinity of −8.645 kcal·mol−1, which was considered an optimal value for the study. The values presented by ligand_033, ligand_013, ligand_044, and ligand_080 meet the profile of novel drugs. To choose compounds with favorable potential for synthesis, synthetic accessibility studies and similarity analyses were carried out. Molecular dynamics and theoretical IC50 values (ranging from 0.459 to 2.371 µM) demonstrate that these candidates are promising for further tests. Chemical descriptors showed that the candidates had strong molecule stability. Theoretical analyses here show that these molecules have potential as SARS-CoV-2 antivirals and therefore warrant further investigation.