Shultz, Michael (2013) Setting expectations in molecular optimizations: Strengths and limitations of commonly used composite parameters. Bioorganic and Medicinal Chemistry Letters, 23 (21). pp. 5980-5991. ISSN 0960-894X

Abstract

Over the past 15 years there have been extensive efforts to understand and reduce the high attrition rates of drug candidates with an increased focus on physicochemical properties. The fruits of this labor have been the generation of numerous efficiency indices, metric-based rules and visualization tools to help guide medicinal chemists in the design of new compounds with more favorable properties. This deluge of information may have had the unintended consequence of further obfuscating molecular optimizations by the inability of these scoring functions, rules and guides to reach a consensus on when a particular transformation is identified as beneficial. In this manuscript, several composite parameters, or efficiency indices, are examined utilizing theoretical and experimental matched molecular pair analyses in order to understand the basis for how each will perform under varying scenarios of molecular optimizations. In contrast to empirically derived composite parameters based on heavy atom count, lipophilic efficiency (LipE) sets consistent expectations regardless of molecular weight or relative potency and can be used to generate consistent expectations for any matched molecular pair. © 2013 Elsevier Ltd. All rights reserved.

Item Type:	Article
Additional Information:	This manuscript contains compounds in two current OAK submissions and provides literature and theoretical analysis.
Keywords:	Composite parameters Efficiency metrics Ligand efficiency Lipophilic efficiency
Date Deposited:	25 Nov 2017 00:45
Last Modified:	25 Jan 2019 00:46
URI:	https://oak.novartis.com/id/eprint/10233