{"doi":"10.1039/d1ob01593a","title":"QM/MM modeling of class A β-lactamases reveals distinct acylation pathways for ampicillin and cefalexin","abstract":"Efficient mechanism-based design of antibiotics that are not susceptible to β-lactamases is hindered by the lack of comprehensive knowledge on the energetic landscapes for the hydrolysis of various β-lactams. Herein, we adopted efficient quantum mechanics/molecular mechanics simulations to explore the acylation reaction catalyzed by CTX-M-44 (Toho-1) β-lactamase. We show that the catalytic pathways for β-lactam hydrolysis are correlated to substrate scaffolds: using Glu166 as the only general base for acylation is viable for ampicillin but prohibitive for cefalexin. The present computational workflow provides quantitative insights to facilitate the optimization of future β-lactam antibiotics.","journal":"Organic & Biomolecular Chemistry","year":2021,"id":201661,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9457,"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":557684,"name":"Francesco Trozzi","orcid":"0000-0001-5538-9189","position":1,"is_corresponding":false},{"id":338702,"name":"Timothy Palzkill","orcid":"0000-0002-5267-0001","position":2,"is_corresponding":false},{"id":566048,"name":"Peng Tao","orcid":"0000-0002-2488-0239","position":3,"is_corresponding":false},{"id":780553,"name":"Zilin Song","orcid":"0000-0002-3127-3971","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-18T23:50:56.394488Z","pmid":"34647114","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":[]}