Medicinal Chemistry in Modern Drug Discovery: Rational Design, Structure–Activity Relationships, And Future Perspectives

Abstract

Medicinal chemistry is a key field in contemporary drug discovery, bringing together the knowledge and understanding of chemical structures and biological activity, therapeutic efficacy, selectivity, pharmacokinetics and safety. The focus of this review is on rational molecular design, structure–activity relationships (SAR), molecular optimisation, structure-based and fragment-based drug discovery, pharmacogenomics, human-relevant models and biomarkers, and how this transition has occurred over the last few years from an empirical approach towards a rational, structure-driven, computational and precision drug design. The evidence reviewed suggests that these methods can be used to enhance target validation, molecular optimisation, compound prioritisation, patient selection, and clinical translation. The molecularly targeted drug designs in human clinical examples such as osimertinib, venetoclax and sotorasib show how important these methods are for human drug discovery, and the upcoming clinical study of rentosertib, an AI-generated inhibitor of TNIK, illustrates the promise of generative AI in the field of modern drug discovery. But there are significant challenges to address, such as biological complexity, patient heterogeneity, drug resistance, computational bias, limited model interpretability and rigorous experimental and clinical validation. As a whole, modern medicinal chemistry is making a transition to an integrated and human-relevant approach in which all aspects of drug development, including chemical, biological, computational, genetic and clinical data, are used to guide more precise, efficient and clinically relevant drug development.