Beckers, Maximilian, Fechner, Nikolas and Stiefl, Nikolaus (2022) 25 Years of Small-Molecule Optimization at Novartis: A Retrospective Analysis of Chemical Series Evolution. Journal of chemical information and modeling, 62 (23). pp. 6002-6021. ISSN 1549-960X

Abstract

In the drug development process, optimization of properties and biological activities of small molecules is an important task to obtain drug candidates with optimal efficacy when first applied in subsequent clinical studies. However, despite its importance, large-scale investigations of the optimization process in early drug discovery are lacking, likely due to the absence of historical records of different chemical series used in past projects. Here, we report a retrospective reconstruction of ∼3000 chemical series from the Novartis compound database, which allows us to characterize the general properties of chemical series as well as the time evolution of structural properties, ADMET properties, and target activities. Our data-driven approach allows us to substantiate common MedChem knowledge. We find that size, fraction of sp3-hybridized carbon atoms (Fsp3), and the density of stereocenters tend to increase during optimization, while the aromaticity of the compounds decreases. On the ADMET side, solubility tends to increase and permeability decreases, while safety-related properties tend to improve. Importantly, while ligand efficiency decreases due to molecular growth over time, target activities and lipophilic efficiency tend to improve. This emphasizes the heavy-atom count and log D as important parameters to monitor, especially as we further show that the decrease in permeability can be explained with the increase in molecular size. We highlight overlaps, shortcomings, and differences of the computationally reconstructed chemical series compared to the series used in recent internal drug discovery projects and investigate the relation to historical projects.

Item Type:	Article
Keywords:	Retrospective Studies Drug Discovery Ligands Solubility Databases, Factual
Date Deposited:	17 Jan 2023 00:45
Last Modified:	17 Jan 2023 00:45
URI:	https://oak.novartis.com/id/eprint/48267