title: Toward understanding the molecular basis for chemical allosteric modulator design.
abstract: Among the regulation mechanisms of cellular function, allosteric regulation is the most direct, rapid and efficient. Due to the wider receptor selectivity and lower target-based toxicity, compared with orthosteric ligands, allosteric modulators are expected to play a larger role in pharmaceutical research and development. However, current difficulties, such as a low affinity and unknown structural features of potential allosteric small-molecules, usually obstruct the discovery of allosteric modulators. In this study, we compared known allosteric modulators with various compounds from different databases to unveil the structural and qualitative characteristics of allosteric modulators. The results show that allosteric modulators generally contain more hydrophobic scaffolds and have a higher structural rigidity, i.e., less rotatable bonds and more rings. Based on this analysis, an empirical rule was defined to determine the structural requirements for an allosteric modulator. It was found that a large proportion of allosteric modulators (80%) can be successfully retrieved by this "allosteric-like" filter, which shows good discriminatory power in identifying allosteric modulators. Therefore, the study provides deeper insight into the chemical properties of allosteric modulators and has a good potential for the design or optimization of allosteric compounds.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Huang
authors.forename: Xinyi
authors.initials: X
authors.lastname: Liu
authors.forename: Huchen
authors.initials: H
authors.lastname: Zhou
authors.forename: Yingyi
authors.initials: Y
authors.lastname: Chen
authors.forename: Ting
authors.initials: T
authors.lastname: Shi
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D062126:Databases, Chemical; D062313:Databases, Pharmaceutical; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D009980:Influenza A virus; D008024:Ligands; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D054852:Small Molecule Libraries / Q000737:chemistry*; D055672:Static Electricity; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors; D000086082:Viroporin Proteins
chemical_list: D008024:Ligands; D011965:Receptors, Glucocorticoid; D054852:Small Molecule Libraries; D013940:Thymidylate Synthase; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins