Trends in small molecule drug properties: A developability molecule assessment perspective

Developability molecule assessment is a key interfacial capability across the biopharmaceutical industry, screening and staging molecules discovered by medicinal chemists for successful chemistry manufacturing controls (CMC) development and launch. The breadth of responsibility and expertise such teams possess puts them in a unique position to understand the impact of the physicochemical properties of a drug during its initial discovery and subsequent development. However, most of the publications describing trends in physicochemical properties are written from a medicinal chemistry perspective with the aim to identify molecules with better ADMET profiles that are either lead-like or drug-like, failing to describe the impact these properties have on CMC development. To systematically uncover knowledge obtained from recent trends in physicochemical properties and the corresponding impact on CMC development, a comprehensive analysis was conducted on molecules in the drug repurposing hub dataset. The only physicochemical property that seems to have been preserved in FDA-approved oral molecules over the decades (1900-2020) is a constant H-bond donor count, highlighting the importance this property has on cell permeability and lattice energy. Pharmaceutical attrition analysis suggests that partition-distribution coefficient, H-bond acceptors, polar surface area and the fraction of sp(3) carbons are properties that are associated with compound attrition. Looking at pharmaceutical attrition asynchronously with the temporal analysis of FDA-approved oral molecules highlights the opposing trends, risks and diminishing effects some of these physiochemical properties (cLogP, cLogD and Fsp(3)) have on describing compound attrition during the past decade. Trellising the dataset by target class suggests that certain formulation and drug delivery strategies can be anticipated or put into place based on target class of a molecule. For example, molecules binding to nuclear hormone receptors are amenable to lipid-based drug delivery systems with proven commercial success. Although the poor solubility of kinase inhibitors is a combination of hydrophobicity (due to aromaticity) required to bind to its target and high lattice energy (melting point), they are a challenging target class to formulate. The influence of drug targets on physicochemical properties and the temporal nature of these properties is highlighted when comparing molecules in the drug repurposing dataset to those developed at Amgen. An improved understanding of the impact of molecular properties on performance attributes can accelerate decisions and facilitate risk assessments during candidate selection and development.

Automated summary

Developability molecule assessment plays a crucial role in the biopharmaceutical industry, helping to screen and rank molecules for successful chemistry manufacturing controls (CMC) development and launch. The impact of physicochemical properties on drug discovery and development is significant, but most publications only focus on medicinal chemistry and fail to consider the influence on CMC development. An analysis of the drug repurposing dataset reveals that the number of hydrogen bond donors is the only physicochemical property consistently preserved in FDA-approved oral molecules over the past century.