Pharmacology seminars

Basic research, technological advances and clinical observations can converge to produce major therapeutic breakthroughs. Examples from lung cancer, spinal muscular atrophy and hemophilia illustrate how curiosity-driven science contributed to medicines including osimertinib, risdiplam and emicizumab. The lecture follows discoveries across the decades between initial biological insights and effective treatments, examining the persistence, unexpected findings and collaboration across disciplines that made these advances possible. It considers how biological, clinical and technological research connect in the development of new medicines.

Digital health technologies generate continuous real-world observations that complement traditional clinical endpoints. This discussion introduces their use throughout drug research, development and commercialization from a clinical pharmacology perspective. It considers how digital observations differ from conventional data, how clinical pharmacology methods help interpret them, common limitations and pitfalls, and their role in regulatory interactions. Examples examine the conversion of wearable and sensor measurements into validated outcomes and the resulting insights into disease and treatment response. The panel also discusses future directions and the potential advantages of adopting these technologies early. ASCPT members attend free. Nonmember registration remains pending until the US$55 fee is arranged by requesting an invoice from ASCPT. Registration closes 15 minutes before the webinar.

Infection research is identifying molecular targets involved in pathogen replication, metabolism and essential host functions, but translating discoveries into treatments requires functional validation. Advances in X-ray crystallography now permit larger-scale screening of fragments and other small molecules against these targets. This seminar presents technologies developed at EMBL Grenoble for fully automated fragment and ligand screening, and their use in investigating infection-related targets with therapeutic potential. It connects structural screening with small-molecule inhibitor development, target validation and evidence for therapeutic feasibility. The session is relevant to infection biology, chemical biology, structural biology and drug discovery.

Drug responses reflect both a ligand’s intrinsic properties and the sensitivity of the biological assay. Receptor abundance and signal-transduction efficiency can therefore alter observed activity and complicate translation from laboratory assays to living systems. Terry Kenakin examines controlled changes in system sensitivity as a way to distinguish the underlying properties of GPCR ligands. Adjusting receptor density and cellular responsiveness permits affinity and efficacy to be assessed within a common operational framework. Lower sensitivity can reveal partial agonism and support estimates of intrinsic efficacy and affinity; further reduction may make weak agonists behave as measurable antagonists. Raising sensitivity can uncover partial or inverse agonism in compounds previously considered neutral antagonists. The presentation also examines how this approach separates allosteric modulation of affinity from effects on efficacy. These methods aim to improve quantitative interpretation of assays and their ability to predict drug activity in vivo, followed by questions and discussion.

Laboratory-evolved gentamicin-resistant bacteria are analysed using whole-genome sequencing and protein-structure modelling. The study focuses on mutations in elongation factor G and compares AlphaFold2 predictions with wild-type proteins. Aligning predicted EF-G structures with experimental ribosome and antibiotic-bound structures reveals how local conformational and physicochemical changes could affect drug binding. The talk examines subtle structural shifts, mutations without detectable structural changes, and the limitations of prediction alone. It presents a workflow that combines genomic evidence, AI models and experimental structures to form mechanistic hypotheses about antimicrobial resistance.

Computational and structure-based vaccine design is examined through two approaches. One uses stabilising mutations to preserve a vaccine antigen in its prefusion conformation; the other extracts epitope information and scaffolds it onto non-antigen protein backbones. The presentation compares the strengths, limitations and potential vaccine-development applications of these strategies. Familiarity with vaccine antigens and viral glycoproteins is helpful, while computational protein-design experience is unnecessary.

Kuan Hong Wang examines how dopaminergic, cannabinoid, and neuroimmune signaling regulate circuit plasticity across development, experience, and disease, and how cross-species work may inform selective therapies.

Interpreting human missense variants requires connecting genomic coordinates with protein sequences, structures and functional evidence. ProtVar integrates annotations and predictions from UniProt, Ensembl, PDBe, Open Targets and AlphaFoldDB, extending variant lookup to discovery across more than 500 million potential missense variants. This seminar demonstrates natural-language searches using diseases, pathways and drug responses, multi-criteria filtering, structural visualisation and data export. Participants will learn to prioritise variants, interpret their structural and functional effects, and retrieve data through web downloads or the REST API. The session serves geneticists, drug-discovery researchers and computational biologists; undergraduate molecular biology and genetics are recommended.