Network-Wide Screen Identifies Variation of Novel Precise On-Module Targets Using Conformational Modudaoism.

Modular targeting is promising in drug research at the network level, but it is challenging to quantificationally identify the precise on-modules. Based on a proposed Modudaoism (MD), we defined conserved MD (MDc) and varied MD (MDv) to quantitatively evaluate the conformational and energy variations of modules, and thereby identify the conserved and discrepant allosteric modules (AMs). Compared to the Zsummary , MDc/MDv got an optimized result of module preserved ratio and modular structure. In the mice anti-ischemic networks, 3, 5, and 1 conserved AMs as well as 4, 1, and 3 on-modules of baicalin (BA), jasminoidin (JA), and ursodeoxycholic acid (UA) were identified by MDc and MDv, 5 unique AMs and their characteristic actions were revealed. Besides, co-immunoprecipitation (Co-IP) experiments validated the representative modular structure. MDc/MDv method can quantitatively define the conformational variations of modules and screen the precise on-modules network-wide, which may provide a promising strategy for drug discovery.