Mining the Synergistic Core Allosteric Modules Variation and Sequencing Pharmacological Module Drivers in a Preclinical Model of Ischemia.

Identifying the variation of core modules and hubs seems to be critical for characterizing variable pharmacological mechanisms based on topological alteration of disease networks. We first identified a total of eight core modules by using an approach of multiple modular characteristic fusing (MMCF) from different targeted networks in ischemic mice. Interestingly, the value of module disturbance intensity (MDI) increased in drug combination group. Second, we redefined a weak allosteric module and a strong allosteric module. Then, we identified 15 pharmacological module drivers (PMDs) by leave-one-out screening with a cutoff of two folds, which were at least, in part, validated by expression and variation of topological contribution. Finally, we revealed the fusional and emergent variation of PMD in core modules contributing to multidimensional synergistic mechanism in ischemic mice and rats. Our findings provide a new set of drivers that might promote the pharmacological modular flexibility and offer a potential avenue for disease treatment.