Where lies the future of Ayurveda-inspired drug discovery?

KEYWORDS:

• Ayurveda
• AyuGenomics
• formulation discovery
• natural products
• reverse pharmacology
• traditional medicine

1. Introduction

The current drug research is in search of newer approaches to improve the precision and efficiency of the discovery process. Artificial intelligence is being explored to improve target identification, drug design, and clinical trial optimization to accelerate the discovery process [1]. We need out-of-the-box thinking to bring disruptive, pathbreaking innovations. Despite advances in biomedical sciences and technology, the rate of new drugs discovered is not increasing. On the contrary, regulators are recalling many drugs for safety reasons. New trends in drug discovery include precision medicine personalized to individual genetic profiles and other factors that can improve safety and efficacy. The COVID-19 pandemic has further stimulated research on natural products and drug repurposing to reduce time and costs [2].

Traditional medicine and natural products remain resourceful for new drug candidates offering a large chemical diversity and a wide range of structures and activities to surpass the target-to-lead bottleneck. However, random screening approach is known to be time-consuming and expensive. Traditional knowledge systems like Ayurveda can help as discovery engines to overcome the innovation deficit in pharmaceutical research [3]. Classical Ayurvedic medicines that are in clinical use for hundreds of years are generally recognized as safe. The correct identification of botanical source, passport data of collection or cultivation, maintaining hygiene, respecting biodiversity, avoiding contamination including pathogens, aflatoxins, heavy metals, and adherence to good manufacturing practices remain crucial. The Ayurvedic Pharmacopoeia of India prescribes standards for the quality, purity, and strength of classical Ayurvedic medicines [4]. However, non-classical, Ayurveda-inspired drugs such as purified extracts, phytopharmaceuticals, isolated bioactive compounds, and novel formulations must follow necessary preclinical and clinical studies to establish safety, quality, and efficacy.

2. Natural products drug discovery

According to the World Health Organization (WHO), about 40% of existing pharmaceutical drugs have originated from traditional medicine [5]. These include not just aspirin, quinine, and such which are historically known, but also relatively recent blockbusters like taxol, metformin, and artemisinin. Natural product extracts consist of a wide range of bioactives and their intermediate compounds produced de-novo during the biosynthesis of secondary metabolites. The various bioactives present in herbal extracts can affect multiple targets or can exert other benefits including improved solubility, bioavailability, and ADME properties. The structural diversity of natural herbal extracts may help in interaction with multiple targets simultaneously. Therefore, scientifically designing synergistic poly herbal formulations may be more relevant, especially for poly genic syndromes.

The one-target one-drug or magic bullet approach was applicable mainly for infectious diseases; however, it may not be sufficient for non-communicable diseases and metabolic syndromes such as cancer, diabetes, obesity, asthma, and metabolic disorders. It is necessary to shift the paradigm to multi-target, multi-drug discovery leading to synergistic formulation.

3. Ayurveda therapeutics

Ayurveda, literally meaning knowledge/science of life in Sanskrit, is an ancient Indian system of medicine. It primarily focuses on health promotion, disease prevention, and diagnosis with detailed guidance about food, nutrition, and lifestyle based on the individual constitution. Ayurveda therapeutics is integrative and personalized that uses dietary and lifestyle modification along with multi-targeted rational synergistic herbo mineral formulations. Ayurveda approach is toward maintenance of homeostasis and regaining natural balance of three humors known as Dosha (Vata, Pitta, and Kapha) also known as Prakriti types. A study on the genetic basis of Dosha Prakriti (pharmaco-phenotype) has emerged as a new discipline known as AyuGenomics® [6]. Synergistic formulation discovery guided by the Prakriti type can address individual variations in therapeutic response and may be more efficient than typical genomic approach.

Ayurveda classics Charaka Samhita and Sushruta Samhita provide detailed descriptions of over 800 medicinal herbs and 8000 herbal-mineral formulations, which are being explored by scientists [7]. Several Ayurveda formulations have remained unchanged for thousands of years. The Ayurvedic database provides knowledge of generally regarded safe botanical material used in its medicines. India’s Traditional Knowledge Digital Library (TKDL, http://www.tkdl.res.in) has data of over 36,000 classical Ayurveda formulations. Around 500 traditional formulations are estimated to be manufactured by various Ayurvedic drug manufacturers and about hundred are popular even at the community level for preventive and primary health care in Indian homes.

4. Reverse pharmacology

The Ayurveda-inspired drug discovery can follow a reverse pharmacology approach from ‘clinics-to-laboratories’ rather than the conventional ‘laboratory-to-clinics’ process. Reverse pharmacology is an approach that integrates reported clinical experiences and experiential observations into leads, through trans-disciplinary exploratory studies. These leads can then be further developed into drug candidates through robust preclinical and clinical studies. In this process, quality and safety is of primary importance, and efficacy is validated using conventional outcome measures [8]. Scientists have identified several bioactive compounds from medicinal plants described in Ayurveda. Examples of these include: Rauwolfia alkaloids for treating hypertension; psoralens for vitiligo; guggulsterons as hypolipidemic agents; Mucuna pruriens for Parkinson’s disease; piperidines as enhancers of bioavailability; baccosides in mental retention; picrosides for hepatic protection; phyllanthins as antivirals; berberine, curcumin for controlling infections, inflammation, and cancer; shatavarins and withanolides as adjuvants and immunomodulators [9].

During COVID-19 pandemic, several Ayurveda drugs and formulations were studied using reverse pharmacology approach [10]. An Ayurvedic formulation Ayush-64 for the treatment of Malaria was repurposed for an adjuvant treatment for mild to moderate cases of COVID-19 [11]. A traditional Ayurvedic formulation Anu Taila, used as intranasal application, showed prophylactic promise with significant antiviral activity, reduction in viral load, and barrier to the entry of virus [12]. In a randomized controlled multi-centric clinical trial, Withania somnifera (Ashwagandha) was shown to be better and safer than hydroxychloroquine for COVID-19 prophylaxis [13].

5. Expert opinion

Scientific advances, especially in cellular, molecular and systems biology, metabolism, omics, and other high throughput technologies, can help to understand the various underlying biological mechanisms to design and discover multi-target synergistic formulations. The classical Ayurveda medicine and natural product libraries can be studied to know the rationale of combinations for discovering new generation synergistic phytopharmaceutical formulations [14].

The WHO Global Centre for Traditional Medicine, established in 2022 at Jamnagar, India, is also encouraging innovative approaches in drug discovery such as reverse pharmacology and Ayugenomics. The epistemological differences in classical Ayurvedic principles and modern drug discovery approach demanding quality assurance, standardization, and scientific evidence for safety and efficacy remain challenging. The traditional knowledge may offer safe materials and novel scaffolds for synthesizing new chemical entities. A new technique known as network pharmacology uses computational power and supercomputer-based virtual high-throughput screening for docking studies and drug repurposing to improve the efficiency of the discovery process. An interesting model based on network pharmacology and bioinformatics can be used to discover new drugs as well as repurpose existing ones [15]. Such innovative approaches based on systems biology, holistic targeting, and traditional medicine can facilitate the transition of drug discovery to synergistic formulation discovery [16].

The formulation development need not be confined to dosage forms and drug delivery systems. The synergistic formulations can be scientifically designed by rationally combining bioactives to address multiple targets. In our opinion, synergistic formulation discovery should follow quality standardization and critical testing for safety and efficacy using conventional methods. In sum, Ayurveda-inspired evidence-based, multi-target synergistic formulation discovery seems to be the future to overcome the impasse and limitations to accelerate the current drug discovery. The science and art of designing synergistic formulations may be the future of drug discovery.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.