Strategies and tactics for optimizing the Hit-to-Lead process and beyond—A computational chemistry perspective

The Hit-to-Lead-to-Candidate process continues to evolve rapidly, and while technological advances offer much potential, the reality often pales to the promise. Conversely, strategies and tactics implementing existing technologies may result in more benefit in the end. This article focuses on some of the thinking and approaches that may improve the efficiency and effectiveness of the beginnings of the drug discovery path. From the perspective of computational chemists, different types of strategy and philosophy of approach will be treated including: considerations of early lead choices, strategies for improving poor leads, multivariate optimization, opportunities for informatics, and engineering good decisions. In pharmaceutical discovery, Hit-to-Lead strategies and processes are rapidly evolving and yet far from mature. A computational chemistry perspective can help projects deal with discovery risks and probabilities, and can help ensure effective decision-making.