Formation of Activity Cliffs Is Accompanied by Systematic Increases in Ligand Efficiency from Lowly to Highly Potent Compounds
Journal Title: The AAPS Journal - Year 2014, Vol 16, Issue 2
Abstract
Activity cliffs (ACs) are defined as pairs of structurally similar compounds sharing the same biological activity but having a large difference in potency. Therefore, ACs are often studied to rationalize structure-activity relationships (SARs) and aid in lead optimization. Hence, the AC concept plays an important role in compound development. For compound optimization, ligand efficiency (LE) represents another key concept. LE accounts for the relation between compound potency and mass. A major goal of lead optimization is to increase potency and also LE. Despite their high relevance for drug development, the AC and LE concepts have thus far not been considered in combination. It is currently unknown how compounds forming ACs might be related in terms of LE. To explore this question, ACs were systematically identified on the basis of high-confidence activity data and LE values for cliff partners were determined. Surprisingly, a significant increase in LE was generally detected for highly potent cliff partners compared to their lowly potent counterparts, regardless of the compound classes and their targets. Hence, ACs reveal chemical modifications that determine SARs and improve LE. These findings further increase the attractiveness of AC information for compound optimization and development.
Authors and Affiliations
Antonio de la Vega de León, Jürgen Bajorath
Keywords
Related Articles
- EP ID EP681066
- DOI 10.1208/s12248-014-9567-x
- Views 77
- Downloads 0
Regional-Dependent Intestinal Permeability and BCS Classification: Elucidation of pH-Related Complexity in Rats Using Pseudoephedrine
Based on its lower Log P value relative to metoprolol, a marker for the low/high-permeability (Peff) class boundary, pseudoephedrine was provisionally classified as BCS low-permeability compound. On the other hand, follo...
Gomisin A is a Novel Isoform-Specific Probe for the Selective Sensing of Human Cytochrome P450 3A4 in Liver Microsomes and Living Cells
The online version of this article (doi:10.1208/s12248-015-9827-4) contains supplementary material, which is available to authorized users.
Bioequivalence; Its History, Practice, and Future
In the United States, the FDA approves and grants marketing authorization of generic drugs by applying the regulatory requirements provided in the Code of Federal Regulations (CFR). The following table provides some of t...
Genotyping and drug response: Use of single nucleotide polymorphisms (SNPs) versus haplotypes to predict albuterol efficacy
A Fast Method for Testing Covariates in Population PK/PD Models
The development of covariate models within the population modeling program like NONMEM is generally a time-consuming and non-trivial task. In this study, a fast procedure to approximate the change in objective function v...