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
The effect of alkylpolyglycoside surfactants on the crystallization of spray-dried salbutamol sulphate: a gravimetric near-infrared spectroscopy study
This study monitored the effect of a series of structurally related surfactants on the crystallization of amorphous salbutamol sulphate. Amorphous salbutamol sulphate was prepared by spray drying from a solution in water...
Online Monitoring of PLGA Microparticles Formation Using Lasentec Focused Beam Reflectance (FBRM) and Particle Video Microscope (PVM)
Knowledge of the effects of different product and process variability on microparticle characterization is essential for the successful development, optimization, and scale-up of an encapsulation process. In the current...
Biological Products for the Treatment of Psoriasis: Therapeutic Targets, Pharmacodynamics and Disease-Drug-Drug Interaction Implications
Psoriasis is a chronic inflammatory skin disease condition that involves altered expression of a broad spectrum of proinflammatory cytokines which are associated with activation of T cells and proliferation of keratinocy...
Assessment of the Impact of Dosing Time on the Pharmacokinetics/Pharmacodynamics of Prednisolone
Prednisolone is widely used for the treatment of inflammation and auto-immune diseases. It exhibits nonlinear pharmacokinetics (PK); and its induced systemic effects (pharmacodynamics (PD)) are commonly evaluated with tw...
A Simplified PBPK Modeling Approach for Prediction of Pharmacokinetics of Four Primarily Renally Excreted and CYP3A Metabolized Compounds During Pregnancy
The online version of this article (doi:10.1208/s12248-013-9505-3) contains supplementary material, which is available to authorized users.