Drugs for allosteric sites on receptors.

By Cody J. Wenthur, P. Gentry, Thomas P Mathews, Craig Lindsley. 2014

245 citations recorded by the source corpus.

The presence of druggable, topographically distinct allosteric sites on a wide range of receptor families has offered new paradigms for small molecules to modulate receptor function. Moreover, ligands that target allosteric sites offer significant advantages over the corresponding orthosteric ligands in terms of selectivity, including subtype selectivity within receptor families, and can also impart improved physicochemical properties. However, allosteric ligands are not a panacea. Many chemical issues (e.g., flat structure-activity relationships) and pharmacological issues (e.g., ligand-biased signaling) that are allosteric centric have emerged. Notably, the fact that allosteric sites are less evolutionarily conserved leads to improved selectivity; however, this can also lead to species differences that can hinder safety assessment. Many allosteric ligands possess molecular switches, wherein a small structural change (chemical or metabolic) can modulate the mode of pharmacology or receptor subtype selectivity. As the field has matured, as described here, key principles and strategies have emerged for the design of ligands/drugs for allosteric sites.

Subfields: Computational Theory and Mathematics, Molecular Biology, Computational Chemistry & Drug Discovery

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In Computational Theory and Mathematics

1. C. K. Surratt
2. Jeffry D. Madura
3. Michael J. Wasko
4. Kendy A. Pellegrene

In Molecular Biology

1. C. K. Surratt
2. Jeffry D. Madura
3. Michael J. Wasko
4. Kendy A. Pellegrene

In Computational Chemistry & Drug Discovery

1. C. K. Surratt
2. Jeffry D. Madura
3. Michael J. Wasko
4. Kendy A. Pellegrene

Citations in the corpus

• A Role for Fragment-Based Drug Design in Developing Novel Lead Compounds for Central Nervous System Targets (2015, background): “Considering the similarities between GPCR orthosteric (primary) binding pockets among not-so-distant family members, the drug design field has turned its focus to secondary or allosteric binding sites (44).”