Designing drugs and chemical probes with the dualsteric approach

Abstract

Dualsteric modulators are praised for a balance of potency and selectivity, overcoming drug resistance, function bias, and an easy scheme for partial agonist. It could also be used to design fluorescent tracers and study protein conformations.

Active Discovery of the Allosteric Inhibitor Targeting Botrytis cinerea Chitinase Based on Neural Relational Inference for Food Preservation

“…A growing body of research suggests the continuous discovery of competitive inhibitors. − Nevertheless, the selective pressure exerted on the pathogen by competitive inhibitors is anticipated to further fortify the resistance of B. cinerea . − Consequently, this sets in motion a detrimental cycle, hindering the advancement of efficacious inhibitors against B. cinerea . In contrast, allosteric inhibitors, distinguished by their unique biological conformational characteristics, emerge as a novel strategy to alleviate the development of resistance in pathogenic microorganism inhibitors . Nonetheless, the limited conformational information available for target proteins hinders the efficiency of allosteric inhibitor development, posing a challenge in meeting practical demands.…”

“…In contrast, allosteric inhibitors, distinguished by their unique biological conformational characteristics, emerge as a novel strategy to alleviate the development of resistance in pathogenic microorganism inhibitors. 52 Nonetheless, the limited conformational information available for target proteins hinders the efficiency of allosteric inhibitor development, 12 posing a challenge in meeting practical demands. In light of these unfavorable factors, we employed a deep learning methodology, specifically the Neural Relational Inference (NRI) model, 32 to scrutinize the potential interactions among domains in the protein target trajectory.…”

Allosteric Modulators of Serotonin Receptors: A Medicinal Chemistry Survey

“…Dualsteric ligands might be considered as a particular subgroup of allosteric modulators. Dualsteric modulators are bivalent (or bitopic) as they feature two pharmacophores; one binds the protein at the orthosteric and the other at an allosteric site [ 96 ]. This type of ligand has recently gained attention as they should combine, at least in theory, high affinity (via the orthosteric site) with high selectivity (via an allosteric site).…”