Analyses

By analysing the physicochemical properties of a database of hits and leads, Keserü and Makara conclude that high-throughput screening, as well as hit-to-lead optimization practices in general, are responsible for the unfavourable physicochemical profile of recent leads and clinical candidates. Major adjustments may be needed to enable a balanced lead-evolution process and reduce the likelihood of high compound-related attrition in clinical trials.

Understanding the molecular mechanisms underlying the effects of efficacious drug combinations could aid the discovery of novel combinations and multi-targeted drugs. This article presents an extensive investigation of drug combinations for which rigorous analytical information is available in published literature, which illustrates several general types of combination mechanisms and highlights the potential value of molecular interaction profiles for studying such mechanisms.

Despite the wide acceptance of drug-like principles such as the 'rule of five', this analysis of molecules currently being synthesized in leading pharmaceutical companies reveals that their physical properties differ significantly from those of recently discovered oral drugs. The marked increase in lipophilicity in particular could increase the likelihood of attrition in drug development.