{"doi":"10.3390/molecules29215081","title":"Cannabinoid-Inspired Inhibitors of the SARS-CoV-2 Coronavirus 2′-O-Methyltransferase (2′-O-MTase) Non-Structural Protein (Nsp10–16)","abstract":"The design and synthesis of antiviral compounds were guided by computationally predicted data against highly conserved non-structural proteins (Nsps) of the SARS-CoV-2 coronavirus. Chromenephenylmethanone-1 (CPM-1), a novel biphenylpyran (BPP), was selected from a unique natural product library based on in silico docking scores to coronavirus Nsps with high specificity to the methyltransferase protein (2′-O-MTase, Nsp10–16), which is responsible for viral mRNA maturation and host innate immune response evasion. To target the 2′-O-MTase, CPM-1, along with intermediate BPP regioisomers, tetrahydrophenylmethanones (TPMs), were synthesized and structurally validated via nuclear magnetic resonance (NMR) data and DP4+ structure probability analyses. To investigate the activity of these BPPs, the following in vitro assays were conducted: SARS-CoV-2 inhibition, biochemical target validation, mutagenicity, and cytotoxicity. CPM-1 possessed notable activity against SARS-CoV-2 with 98.9% inhibition at 10 µM and an EC50 of 7.65 µM, as well as inhibition of SARS-CoV-2’s 2′-O-MTase (expressed and purified) with an IC50 of 1.5 ± 0.2 µM. In addition, CPM-1 revealed no cytotoxicity (CC50 of >100 µM) or mutagenicity (no frameshift or base-pair mutations). This study demonstrates the potential of computational modeling for the discovery of natural product prototypes followed by the design and synthesis of drug leads to inhibit the SARS-CoV-2 2′-O-MTase.","journal":"Molecules","year":2024,"id":505369,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9529,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":891909,"name":"George S. Hanna","orcid":"0000-0001-7616-064X","position":1,"is_corresponding":false},{"id":909256,"name":"Cody F. Dickinson","orcid":"0000-0003-1318-4438","position":2,"is_corresponding":false},{"id":890547,"name":"Yeun‐Mun Choo","orcid":"0000-0001-9891-5898","position":3,"is_corresponding":false},{"id":1356349,"name":"Xiaojuan Wang","orcid":"0000-0001-5559-6997","position":4,"is_corresponding":false},{"id":314481,"name":"Jessica Downs-Bowen","orcid":"0000-0002-7472-033X","position":5,"is_corresponding":false},{"id":929758,"name":"Ramyani De","orcid":"0000-0001-5534-0705","position":6,"is_corresponding":false},{"id":315999,"name":"Tamara R. McBrayer","orcid":null,"position":7,"is_corresponding":false},{"id":228075,"name":"Raymond F. Schinazi","orcid":"0000-0002-6688-3614","position":8,"is_corresponding":false},{"id":1356629,"name":"Sarah E. Nielson","orcid":null,"position":9,"is_corresponding":false},{"id":1356350,"name":"Joan M. Hevel","orcid":"0000-0002-9559-4635","position":10,"is_corresponding":false},{"id":364209,"name":"Pankaj Pandey","orcid":"0000-0001-9128-8254","position":11,"is_corresponding":false},{"id":364210,"name":"Robert J. Doerksen","orcid":"0000-0002-3789-1842","position":12,"is_corresponding":false},{"id":426398,"name":"Danyelle M. Townsend","orcid":"0000-0003-4679-1891","position":13,"is_corresponding":false},{"id":402931,"name":"Jie Zhang","orcid":"0000-0001-6717-4118","position":14,"is_corresponding":false},{"id":737725,"name":"Zhiwei Ye","orcid":"0000-0001-7537-2739","position":15,"is_corresponding":false},{"id":891092,"name":"Scott Wyer","orcid":null,"position":16,"is_corresponding":false},{"id":1356351,"name":"Lucas Bialousow","orcid":"0000-0003-1126-8670","position":17,"is_corresponding":false},{"id":510003,"name":"Mark T. Hamann","orcid":"0000-0002-3798-4002","position":18,"is_corresponding":false},{"id":666950,"name":"Menny M. Benjamin","orcid":"0000-0002-0212-3405","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T02:10:47.170978Z","pmid":"39519722","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":[]}