{"doi":"10.1101/2021.04.02.438204","title":"Discovery and in-vitro evaluation of potent SARS-CoV-2 entry inhibitors","abstract":"Abstract SARS-CoV-2 infection initiates with the attachment of spike protein to the ACE2 receptor. While vaccines have been developed, no SARS-CoV-2 specific small molecule inhibitors have been approved. Herein, utilizing the crystal structure of the ACE2/Spike receptor binding domain (S-RBD) complex in computer-aided drug design (CADD) approach, we docked ∼8 million compounds within the pockets residing at S-RBD/ACE2 interface. Five best hits depending on the docking score, were selected and tested for their in vitro efficacy to block SARS-CoV-2 replication. Of these, two compounds (MU-UNMC-1 and MU-UNMC-2) blocked SARS-CoV-2 replication at sub-micromolar IC 50 in human bronchial epithelial cells (UNCN1T) and Vero cells. Furthermore, MU-UNMC-2 was highly potent in blocking the virus entry by using pseudoviral particles expressing SARS-CoV-2 spike. Finally, we found that MU-UNMC-2 is highly synergistic with remdesivir (RDV), suggesting that minimal amounts are needed when used in combination with RDV, and has the potential to develop as a potential entry inhibitor for COVID-19.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":218599,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9383,"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":297034,"name":"Kabita Pandey","orcid":null,"position":1,"is_corresponding":false},{"id":476978,"name":"Michellie Thurman","orcid":"0000-0002-7699-1870","position":2,"is_corresponding":false},{"id":634096,"name":"Elizabeth Klug","orcid":"0000-0003-3689-6104","position":3,"is_corresponding":false},{"id":322790,"name":"Jay Trivedi","orcid":"0000-0001-5721-9204","position":4,"is_corresponding":false},{"id":393416,"name":"Christian L. Lorson","orcid":"0000-0002-1023-2169","position":5,"is_corresponding":false},{"id":231042,"name":"Kamalendra Singh","orcid":"0000-0002-3031-5260","position":6,"is_corresponding":false},{"id":69434,"name":"Siddappa N. Byrareddy","orcid":"0000-0002-6889-4640","position":7,"is_corresponding":false},{"id":296005,"name":"Arpan Acharya","orcid":"0000-0003-2721-1062","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:29.626149Z","pmid":"33821265","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":[]}