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Allosteric modulators (AM) that bind allosteric sites can exhibit greater selectivity than the orthosteric ligands and can either enhance agonist-induced receptor activity (termed positive allosteric modulator, or PAM), inhibit agonist-induced activity (negative AM, or NAM), or have no effect on activity (silent AM, or SAM). Until now, it is not clear what the exact effects of AMs are on the orthosteric active site or the allosteric binding pocket(s). In the present work, we collected both the 3D structures of receptor-orthosteric ligand and receptor-orthosteric ligand-AM complexes of a specific target protein. Using our novel algorithm toolset-Molecular Complex Characterizing System (MCCS), we were able to quantify the key residues in both the orthosteric and allosteric binding sites along with potential changes of the binding pockets. After analyzing 21 pairs of 3D crystal or 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 that the binding of AMs had little impact on both the orthosteric- and allosteric- binding pockets. In return, given the accurately predicted allosteric binding pocket(s) on a drug target of medicinal interest, we can confidently conduct the virtual screening or lead optimization without concern that the huge conformational change of the pocket could lead to the low accuracy of virtual screening.

Allosteric modulators (AM) that bind allosteric sites can exhibit greater selectivity than the orthosteric ligands and can either enhance agonist-induced receptor activity (termed positive allosteric modulator, or PAM), inhibit agonist-induced activity (negative AM, or NAM), or have no effect on activity (silent AM, or SAM). Until now, it is not clear what the exact effects of AMs are on the orthosteric active site or the allosteric binding pocket(s). In the present work, we collected both the 3D structures of receptor-orthosteric ligand and receptor-orthosteric ligand-AM complexes of a specific target protein. Using our novel algorithm toolset-Molecular Complex Characterizing System (MCCS), we were able to quantify the key residues in both the orthosteric and allosteric binding sites along with potential changes of the binding pockets. After analyzing 21 pairs of 3D crystal or 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 that the binding of AMs had little impact on both the orthosteric- and allosteric- binding pockets. In return, given the accurately predicted allosteric binding pocket(s) on a drug target of medicinal interest, we can confidently conduct the virtual screening or lead optimization without concern that the huge conformational change of the pocket could lead to the low accuracy of virtual screening.