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How Do Modulators Affect the Orthosteric and Allosteric BindingPockets?
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DOI：10.1021/acschemneuro.1c00749.png)
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Abstract
En 中文
Allosteric modulators (AMs) that bind allostericsites can exhibit greater selectivity than the orthosteric ligands andcan either enhance agonist-induced receptor activity (termedpositive allosteric modulator or PAM), inhibit agonist-inducedactivity (negative AM or NAM), or have no effect on activity(silent AM or SAM). Until now, it is not clear what the exacteffects of AMs are on the orthosteric active site or the allostericbinding pocket(s). In the present work, we collected both thethree-dimensional (3D) structures of receptor-orthosteric ligandand receptor-orthosteric ligand-AM complexes of a specifictarget protein. Using our novel algorithm toolset, molecularcomplex characterizing system (MCCS), we were able to quantifythe key residues in both the orthosteric and allosteric binding sitesalong with potential changes of the binding pockets. After analyzing 21 pairs of 3D crystal or cryo-electron microscopy (cryo-EM)complexes, including 4 pairs of GPCRs, 5 pairs of ion channels, 11 pairs of enzymes, and 1 pair of transcription factors, we found thatthe binding of AMs had little impact on both the orthosteric and allosteric binding pockets. In return, given the accurately predictedallosteric binding pocket(s) of a drug target of medicinal interest, we can confidently conduct the virtual screening or leadoptimization without concern that the huge conformational change of the pocket could lead to the low accuracy of virtual screening
Keywords:
allosteric modulator
MCCS
drug discovery
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