PMID- 35107459 OWN - NLM STAT- MEDLINE DCOM- 20220218 LR - 20221207 IS - 1463-9084 (Electronic) IS - 1463-9076 (Linking) VI - 24 IP - 7 DP - 2022 Feb 16 TI - A multiple-step in silico screening protocol to identify allosteric inhibitors of Spike-hACE2 binding. PG - 4305-4316 LID - 10.1039/d1cp04736a [doi] AB - While the COVID-19 pandemic continues to worsen, effective medicines that target the life cycle of SARS-CoV-2 are still under development. As more highly infective and dangerous variants of the coronavirus emerge, the protective power of vaccines will decrease or vanish. Thus, the development of drugs, which are free of drug resistance is direly needed. The aim of this study is to identify allosteric binding modulators from a large compound library to inhibit the binding between the Spike protein of the SARS-CoV-2 virus and human angiotensin-converting enzyme 2 (hACE2). The binding of the Spike protein to hACE2 is the first step of the infection of host cells by the coronavirus. We first built a compound library containing 77 448 antiviral compounds. Molecular docking was then conducted to preliminarily screen compounds which can potently bind to the Spike protein at two allosteric binding sites. Next, molecular dynamics simulations were performed to accurately calculate the binding affinity between the spike protein and an identified compound from docking screening and to investigate whether the compound can interfere with the binding between the Spike protein and hACE2. We successfully identified two possible drug binding sites on the Spike protein and discovered a series of antiviral compounds which can weaken the interaction between the Spike protein and hACE2 receptor through conformational changes of the key Spike residues at the Spike-hACE2 binding interface induced by the binding of the ligand at the allosteric binding site. We also applied our screening protocol to another compound library which consists of 3407 compounds for which the inhibitory activities of Spike/hACE2 binding were measured. Encouragingly, in vitro data supports that the identified compounds can inhibit the Spike-ACE2 binding. Thus, we developed a promising computational protocol to discover allosteric inhibitors of the binding of the Spike protein of SARS-CoV-2 to the hACE2 receptor, and several promising allosteric modulators were discovered. FAU - Zhai, Jingchen AU - Zhai J AUID- ORCID: 0000-0003-2691-8867 AD - Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. junmei.wang@pitt.edu. FAU - He, Xibing AU - He X AUID- ORCID: 0000-0001-7431-7893 AD - Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. junmei.wang@pitt.edu. FAU - Man, Viet Hoang AU - Man VH AUID- ORCID: 0000-0002-8907-6479 AD - Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. junmei.wang@pitt.edu. FAU - Sun, Yuchen AU - Sun Y AUID- ORCID: 0000-0001-9936-0476 AD - Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. junmei.wang@pitt.edu. FAU - Ji, Beihong AU - Ji B AUID- ORCID: 0000-0003-0387-4056 AD - Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. junmei.wang@pitt.edu. FAU - Cai, Lianjin AU - Cai L AUID- ORCID: 0000-0001-5354-4050 AD - Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. junmei.wang@pitt.edu. FAU - Wang, Junmei AU - Wang J AUID- ORCID: 0000-0002-9607-8229 AD - Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. junmei.wang@pitt.edu. LA - eng PT - Journal Article DEP - 20220216 PL - England TA - Phys Chem Chem Phys JT - Physical chemistry chemical physics : PCCP JID - 100888160 RN - 0 (Spike Glycoprotein, Coronavirus) RN - 0 (spike protein, SARS-CoV-2) RN - EC 3.4.17.23 (ACE2 protein, human) RN - EC 3.4.17.23 (Angiotensin-Converting Enzyme 2) SB - IM MH - Angiotensin-Converting Enzyme 2/*antagonists & inhibitors MH - Humans MH - Molecular Docking Simulation MH - Pandemics MH - Protein Binding MH - SARS-CoV-2 MH - *Spike Glycoprotein, Coronavirus/antagonists & inhibitors MH - *COVID-19 Drug Treatment EDAT- 2022/02/03 06:00 MHDA- 2022/02/19 06:00 CRDT- 2022/02/02 12:14 PHST- 2022/02/03 06:00 [pubmed] PHST- 2022/02/19 06:00 [medline] PHST- 2022/02/02 12:14 [entrez] AID - 10.1039/d1cp04736a [doi] PST - epublish SO - Phys Chem Chem Phys. 2022 Feb 16;24(7):4305-4316. doi: 10.1039/d1cp04736a.