Abstract

Reverse Pharmacology and Systems Approaches for Drug Discovery and Development: Inspiration from Mother Nature and the Wisdom of the Sages

Mukund Chorghade, President & CSO, Chorghade Enterprises / THINQ Pharma

While biotechnological advances, genomics and high throughput screenings or combinatorial and asymmetric syntheses have long promised new vistas in drug discovery, the pharmaceutical industry is facing a serious innovation deficit. Critics suggest that “we have become high throughput in technology, yet have remained low throughput in thinking”. Post marketing failures of blockbuster drugs have become major concerns of industries, leading to a significant shift in favor of single to multi targeted drugs and affording greater respect to traditional knowledge. Typical reductionist approach of modern science is being revisited over the background of systems biology and holistic approaches of traditional practices. Scientifically validated and technologically standardized botanical products may be explored on a fast track using innovative approaches like reverse pharmacology and systems biology, which are based on traditional medicine knowledge. Traditional medicine constitutes an evolutionary process as communities and individuals continue to discover practices transforming techniques. Many modern drugs have origin in ethnopharmacology and traditional medicine. Ayurveda knowledge and experiential databases can provide new functional leads to reduce time, money and toxicity - the three main hurdles in the drug development. We begin the search based on Ayurvedic medicine research, clinical experiences, observations or available data on actual use in patients as a starting point. We use principles of systems biology where holistic yet rational analysis is done to address multiple therapeutic requirements. Since safety of the materials is already established from traditional use track record, we undertake pharmaceutical development, safety validation and pharmacodynamic studies in parallel to controlled clinical studies. Thus, drug discovery based on Ayurveda follows a ‘Reverse Pharmacology’ path from Clinics to Laboratories. Herein we describe such approaches with selected examples based on previous studies.

Traditional Medicine (Complimentary Alternate Medicine to the Western World) has historically involved clinical use of extracts, powders and other formulations. The extracts have not been standardized, the pure chemical products have rarely been isolated, the biological mechanisms of action have not been elucidated and the clinical trials have rarely been controlled and documented to international standards. Our goals are to discover and develop these medicines to international standards and introduce them globally after appropriate regulatory filings.

THINQ’s natural product discovery programs utilize biologically active natural products as an advanced starting point for discovery. NPs can be considered “pre-validated by nature”, having been optimized for interaction with biological macromolecules through evolutionary selection processes. Embedded in these bioactive natural products are several diverse, chiral functional groups which are potential sites for protein binding. This diverse source of novel, active agents serve as leads/scaffolds for elaboration into desperately needed efficacious drugs for a multitude of disease indications. We aim to reconfigure products into chemical hybrid “Molecular Legos” and to screen the deck of diverse compounds against targets.