{"doi":"10.1021/acs.jcim.3c00780","title":"Non-β Lactam Inhibitors of the Serine β-Lactamase blaCTX-M15 in Drug-Resistant <i>Salmonella typhi</i>","abstract":"β-lactamase protein. 74 compounds from computational screening reported in our previous study against β-lactamase CMY-10 were subjected to docking studies against blaCTX-M15. Site-Identification by Ligand Competitive Saturation (SILCS)-Monte Carlo (SILCS-MC) was applied to the top two ligands selected from molecular docking studies to predict and refine their conformations for binding conformations against blaCTX-M15. The SILCS-MC method predicted affinities of -8.6 and -10.7 kcal/mol for Top1 and Top2, respectively, indicating low micromolar binding to the blaCTX-M15 active site. MD simulations initiated from SILCS-MC docked orientations were carried out to better characterize the dynamics and stability of the complexes. Important interactions anchoring the ligand within the active site include pi-pi stacked, amide-pi, and pi-alkyl interactions. Simulations of the Top2-blaCTX-M15 complex exhibited stability associated with a wide range of hydrogen-bond and aromatic interactions between the protein and the ligand. Experimental β-lactamase (BL) activity assays showed that Top1 has 0.1 u/mg BL activity, and Top2 has a BL activity of 0.038 u/mg with a minimum inhibitory concentration of 1 mg/mL. The inhibitors proposed in this study are non-β-lactam-based β-lactamase inhibitors that exhibit the potential to be used in combination with β-lactam antibiotics against multidrug-resistant clinical isolates. Thus, Top1 and Top2 represent lead compounds that increase the efficacy of β-lactam antibiotics with a low dose concentration.","journal":"Journal of Chemical Information and Modeling","year":2023,"id":379130,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9481,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1144006,"name":"Nousheen Parvaiz","orcid":null,"position":1,"is_corresponding":false},{"id":309315,"name":"Alexander D. MacKerell","orcid":"0000-0001-8287-6804","position":2,"is_corresponding":false},{"id":1143574,"name":"Syed Sikander Azam","orcid":"0000-0001-5624-6120","position":3,"is_corresponding":false},{"id":1143573,"name":"Faisal Ahmad","orcid":"0000-0001-7483-361X","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T01:16:52.622552Z","pmid":"37847018","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":[]}