Mapping drug-target interactions and synergy in multi-molecular therapeutics for pressure-overload cardiac hypertrophy

Aparna Rai,Vibin Ramakrishnan,Vikas Kumar,C C Kartha,Gaurav Jerath

doi:10.1038/s41540-021-00171-z

Abstract

Advancements in systems biology have resulted in the development of network pharmacology, leading to a paradigm shift from “one-target, one-drug” to “target-network, multi-component therapeutics”. We employ a chimeric approach involving in-vivo assays, gene expression analysis, cheminformatics, and network biology to deduce the regulatory actions of a multi-constituent Ayurvedic concoction, Amalaki Rasayana (AR) in animal models for its effect in pressure-overload cardiac hypertrophy. The proteomics analysis of in-vivo assays for Aorta Constricted and Biologically Aged rat models identify proteins expressed under each condition. Network analysis mapping protein–protein interactions and synergistic actions of AR using multi-component networks reveal drug targets such as ACADM, COX4I1, COX6B1, HBB, MYH14, and SLC25A4, as potential pharmacological co-targets for cardiac hypertrophy. Further, five out of eighteen AR constituents potentially target these proteins. We propose a distinct prospective strategy for the discovery of network pharmacological therapies and repositioning of existing drug molecules for treating pressure-overload cardiac hypertrophy.

Highlights

Modern medicine is primarily driven by the discovery of smallmolecule entities with pharmacological actions[1]
We have identified Amalaki Rasayana (AR), a concoction used for the treatment of cardiovascular diseases, diabetes, and rejuvenation therapies in Ayurveda, with an objective to re-invent its efficacy through established analytical procedures of modern medicine
In an earlier experiment, spanning a total period of 21 months, we considered two groups of Wistar rats; (i) Aorta Constricted (AC) with pressureoverload left ventricular cardiac hypertrophy (LVCH), induced by clipping ascending Aorta with titanium clips, and (ii) Biologically Aged (BA) rats (Fig. 1a)

Summary

Introduction

Modern medicine is primarily driven by the discovery of smallmolecule entities with pharmacological actions[1]. The “one drug, one target” mode of drug action cannot generally lead to multiple effects in complex or multifactorial diseases because of the underlying complexity of biological networks[2,3,4,5]. The emerging tools of network medicine offer a platform to explore the molecular complexity of a particular disease, leading to the identification of disease modules and pathways, and in investigating molecular defects among apparently distinct pathological phenotypes[6,7,8]. A sensible approach for the treatment of complex diseases is to have a combinatorial drug with constituents that target multiple pathways in a disease-specific network[9,10]

Objectives

Methods

Conclusion