Since completion of the Human Genome Project at the turn of the century, there have been significant advances in genomic technologies together with genomics research. At the same time, the gap between biomedical discovery and clinical application has narrowed through translational medicine, so establishing the era of personalised medicine. In bridging these two disciplines, the clinician-scientist has become an integral part of modern practice. Surgeons and surgical diseases have been less represented than physicians and medical conditions among clinician-scientists and research. Here, we explore the possible reasons for this and propose strategies for moving forward. Discovery-driven personalised medicine is both the present and the future of clinical patient care worldwide, and South Africa is uniquely placed to build capacity for biomedical discovery in Africa. Diverse engagement across clinical disciplines, including surgery, is necessary in order to integrate modern medicine into a developing-world contextualised perspective.
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J Med Chem
January 2025
Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China.
Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether and biaryl as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CL compounds while maintaining a WT selectivity margin.
View Article and Find Full Text PDFJ Chem Theory Comput
January 2025
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Computer-aided drug discovery (CADD) utilizes computational methods to accelerate the identification and optimization of potential drug candidates. Free energy perturbation (FEP) and thermodynamic integration (TI) play a critical role in predicting differences in protein binding affinities between drug molecules. Here, we implement SPONGE-FEP, which incorporates selective integrated tempering sampling (SITS) to enhance sampling efficiency and contains an automated workflow for relative binding free energy (RBFE) calculations.
View Article and Find Full Text PDFClin Pharmacol Ther
January 2025
Department of Pharmacology, Center for Pharmacogenomics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Clopidogrel, an anti-platelet drug, is used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic events, with African Americans (AA) suffering disproportionately. The aim of this study was to discover novel biomarkers of clopidogrel resistance in African Americans using genome and transcriptome data.
View Article and Find Full Text PDFA more complete map of the pattern of genetic variation among inbred mouse strains is essential for characterizing the genetic architecture of the many available mouse genetic models of important biomedical traits. Although structural variants (SVs) are a major component of genetic variation, they have not been adequately characterized among inbred strains due to methodological limitations. To address this, we generated high-quality long-read sequencing data for 40 inbred strains; and designed a pipeline to optimally identify and validate different types of SVs.
View Article and Find Full Text PDFBackgrounds: Biomedical research requires sophisticated understanding and reasoning across multiple specializations. While large language models (LLMs) show promise in scientific applications, their capability to safely and accurately support complex biomedical research remains uncertain.
Methods: We present , a novel question-and-answer benchmark for evaluating LLMs in biomedical research.
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