The changing landscape of medicinal chemistry optimization

Rácz, Anita and Mihalovits, Levente Márk and Beckers, Maximilian and Fechner, Nikolas and Stiefl, Nikolaus and Sirockin, Finton and McCoull, William and Evertsson, Emma and Lemurell, Malin and Makara, Gergely and Keserű, György Miklós (2025) The changing landscape of medicinal chemistry optimization. NATURE REVIEWS DRUG DISCOVERY. No. 8543. ISSN 1474-1776

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Abstract

The goal of a small-molecule drug discovery campaign is the development of chemical entities that fulfil the criteria of the target product profile for progression into clinical trials. This objective is realized through multiparameter medicinal chemistry optimization, typically by identifying the compounds at the hit stage with molecular properties that provide a high chance of subsequent success, and then iteratively optimizing the properties, often in parallel, to identify leads and, ultimately, drug candidates. To assess the impact of medicinal chemistry optimizations on molecular properties, a set of new drug candidates reported in the literature between 2015 and 2022, and their corresponding hit and lead compounds, were analysed, and compared with a set of drug candidates identified between 2000 and 2010, and their corresponding hits and leads. This analysis was complemented by similar analyses of the internal medicinal chemistry programmes pursued at AstraZeneca and Novartis. Here, we highlight and discuss the implications of the observed trends, which include shifts in key physicochemical properties and strategic changes in medicinal chemistry programmes.

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