Conformational restriction: an effective tactic in 'follow-on'-based drug discovery

Abstract

The conformational restriction (rigidification) of a flexible ligand has often been a commonly used strategy in drug design, as it can minimize the entropic loss associated with the ligand adopting a preferred conformation for binding, which leads to enhanced potency for a given physiological target, improved selectivity for isoforms and reduced the possibility of drug metabolism. Therefore, the application of conformational restriction strategy is a core aspect of drug discovery and development that is widely practiced by medicinal chemists either deliberately or subliminally. The present review will highlight current representative examples and a brief overview on the rational design of conformationally restricted agents as well as discuss its advantages over the flexible counterparts.

Drug discovery beyond the rule of 5 - Opportunities and challenges

“…Conformational restriction is widely utilized to design potent and selective drugs as flexible ligands suffer an entropic penalty upon target binding due to restriction of rotatable bonds [10]. At first glance, this appears to be in conflict with the requirement of bRo5 drugs to possess some flexibility in order to balance cell permeability and solubility.…”

Novel fluorine-containing DAPY derivatives as potent HIV-1 NNRTIs: a patent evaluation of WO2014072419

“…Lastly and most importantly, the stereochemical diversityoriented conformational restriction strategy, allowing the emergence of a collection of enantiopure molecules, could improve efficacy and manage drug-induced mutations [56]. With the advent of safe and selective fluorinating agents and rapid development of the synthesis methodology of asymmetric fluorination [57,58], there is still great scope for the exploitation of compounds featuring a fluorine atom on (or around) a suitable stereocenter in the key pharmacophoric site of promising NNRTI scaffolds.…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…However, proteins are quite flexible and undergo conformational changes during an induced fitting with a flexible binder. Besides, a single compound can show more than one conformation, so, based on the available three‐dimensional structures, a strategy of constraining the conformation of flexible molecules (eg, forming a macrocycle between two solvent‐exposed substituent positions of a given binder) is well‐established to improve potency, selectivity, and PKs or absorption, distribution, metabolism, and excretion (ADME)‐relatedproperties (eg, metabolic stability), while having a minimal effect on the therapeutically relevant binding interaction …”