{"doi":"10.1021/acsptsci.1c00176","title":"Hybrid <i>In Silico</i> Approach Reveals Novel Inhibitors of Multiple SARS-CoV-2 Variants","abstract":"The National Center for Advancing Translational Sciences (NCATS) has been actively generating SARS-CoV-2 high-throughput screening data and disseminates it through the OpenData Portal (https://opendata.ncats.nih.gov/covid19/). Here, we provide a hybrid approach that utilizes NCATS screening data from the SARS-CoV-2 cytopathic effect reduction assay to build predictive models, using both machine learning and pharmacophore-based modeling. Optimized models were used to perform two iterative rounds of virtual screening to predict small molecules active against SARS-CoV-2. Experimental testing with live virus provided 100 (∼16% of predicted hits) active compounds (efficacy > 30%, IC50 ≤ 15 μM). Systematic clustering analysis of active compounds revealed three promising chemotypes which have not been previously identified as inhibitors of SARS-CoV-2 infection. Further investigation resulted in the identification of allosteric binders to host receptor angiotensin-converting enzyme 2; these compounds were then shown to inhibit the entry of pseudoparticles bearing spike protein of wild-type SARS-CoV-2, as well as South African B.1.351 and UK B.1.1.7 variants.","journal":"ACS Pharmacology & Translational Science","year":2021,"id":181497,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9463,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":365516,"name":"Daniel C. Talley","orcid":null,"position":1,"is_corresponding":false},{"id":228430,"name":"Bolormaa Baljinnyam","orcid":"0000-0001-9548-4965","position":2,"is_corresponding":false},{"id":732413,"name":"Jun Choe","orcid":"0000-0002-3389-5969","position":3,"is_corresponding":false},{"id":550314,"name":"Quinlin Hanson","orcid":"0000-0001-6033-8415","position":4,"is_corresponding":false},{"id":287615,"name":"Wei Zhu","orcid":"0000-0003-1165-634X","position":5,"is_corresponding":false},{"id":227989,"name":"Miao Xu","orcid":"0000-0001-9968-733X","position":6,"is_corresponding":false},{"id":227988,"name":"Catherine Z. Chen","orcid":"0000-0002-6900-6553","position":7,"is_corresponding":false},{"id":227992,"name":"Wei Zheng","orcid":"0000-0003-1034-0757","position":8,"is_corresponding":false},{"id":267852,"name":"Xin Hu","orcid":"0000-0003-1164-5130","position":9,"is_corresponding":false},{"id":239789,"name":"Min Shen","orcid":"0000-0002-8218-0433","position":10,"is_corresponding":false},{"id":268294,"name":"Ganesha Rai","orcid":"0000-0001-9763-9641","position":11,"is_corresponding":false},{"id":255126,"name":"Matthew D. Hall","orcid":"0000-0002-5073-442X","position":12,"is_corresponding":false},{"id":228423,"name":"Anton Simeonov","orcid":"0000-0002-4523-9977","position":13,"is_corresponding":false},{"id":12541,"name":"Alexey Zakharov","orcid":"0000-0003-2466-1711","position":14,"is_corresponding":false},{"id":636400,"name":"Sankalp Jain","orcid":"0000-0002-9370-9611","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-18T23:48:05.146883Z","pmid":"34608449","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}