Integrated Screening for Beta-Lactamases Inhibitors Identification of Pharmaceutical Hits and Lead Optimization

Beta-lactamase is an enzyme that is involved in drug resistance. Penicillin like antibiotics constitute 60 % of worldwide antibiotic usage. Bacterial cells use beta lactamase to resist penicillin like antibiotics. Employing computer software programs (two different programs); we have generated a model to produce docking studies data using nine different criteria evaluating the virtual compounds. The virtual compounds that we employ are drug like, similar in chemical moieties to known inhibitors, contain privileged structures and are readily available to purchase to test in vitro. Then using a pivot table from excel the duplicates of the virtual compounds with the binding criteria is revealed. Docking studies reveal how tight the virtual compounds are binding at the active site along with structural (the pose at the active site), kinetic data we are searching for a pharmacological hit. Recently we discovered a compound Ractopamine that shows micro molar activity in vitro. Currently we have shown that a potential cancer drug (LG100268) has low micro molar activity in vitro. Eventually after optimizing our pharmaceutical hits with different virtual compounds, we will use synthetic organic chemistry, molecular modeling, and structure activity relationships to advance the projects into lead and drug space with acceptable pharmacokinetic properties

Germline Variants Incidentally Detected via Tumor-Only Genomic Profiling of Patients with Mesothelioma

Importance: Patients with mesothelioma often have next-generation sequencing (NGS) of their tumor performed; tumor-only NGS may incidentally identify germline pathogenic or likely pathogenic (P/LP) variants despite not being designed for this purpose. It is unknown how frequently patients with mesothelioma have germline P/LP variants incidentally detected via tumor-only NGS. Objective: To determine the prevalence of incidental germline P/LP variants detected via tumor-only NGS of mesothelioma.Design, Setting, and Participants: A series of 161 unrelated patients with mesothelioma from a high-volume mesothelioma program had tumor-only and germline NGS performed during April 2016 to October 2021. Follow-up ranged from 18 months to 7 years. Tumor and germline assays were compared to determine which P/LP variants identified via tumor-only NGS were of germline origin. Data were analyzed from January to March 2023.Main Outcomes and Measures: The proportion of patients with mesothelioma who had P/LP germline variants incidentally detected via tumor-only NGS.Results: Of 161 patients with mesothelioma, 105 were male (65%), the mean (SD) age was 64.7 (11.2) years, and 156 patients (97%) self-identified as non-Hispanic White. Most (126 patients [78%]) had at least 1 potentially incidental P/LP germline variant. The positive predictive value of a potentially incidental germline P/LP variant on tumor-only NGS was 20%. Overall, 26 patients (16%) carried a P/LP germline variant. Germline P/LP variants were identified in ATM, ATR, BAP1, CHEK2, DDX41, FANCM, HAX1, MRE11A, MSH6, MUTYH, NF1, SAMD9L, and TMEM127.Conclusions and Relevance: In this case series of 161 patients with mesothelioma, 16% had confirmed germline P/LP variants. Given the implications of a hereditary cancer syndrome diagnosis for preventive care and familial counseling, clinical approaches for addressing incidental P/LP germline variants in tumor-only NGS are needed. Tumor-only sequencing should not replace dedicated germline testing. Universal germline testing is likely needed for patients with mesothelioma.</p