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

Area of Science:

• Systems biology
• Pharmacology
• Network pharmacology

Background:

• Identifying precise drug targets in biological networks is crucial but challenging.
• Modular targeting offers a promising strategy for drug research at the network level.

Purpose of the Study:

• To develop a quantitative method for identifying conserved and discrepant allosteric modules (AMs) and on-modules.
• To evaluate the effectiveness of the Modudaoism (MD) framework in drug discovery.

Main Methods:

• Defined conserved MD (MDc) and varied MD (MDv) to quantitatively assess module conformational and energy variations.
• Applied MDc/MDv to mice anti-ischemic networks for identifying AMs and on-modules of specific drugs.
• Validated findings using co-immunoprecipitation (Co-IP) experiments.

Main Results:

• MDc/MDv provided optimized results for module preserved ratio and modular structure compared to Z_summary.
• Identified conserved AMs and on-modules for baicalin, jasminoidin, and ursodeoxycholic acid in mice anti-ischemic networks.
• Revealed 5 unique AMs and their characteristic actions, with Co-IP validating the modular structure.

Conclusions:

• The MDc/MDv method quantitatively defines module conformational variations and screens precise on-modules network-wide.
• This approach offers a promising strategy for network-level drug discovery and target identification.