Natural Products in Drug Discovery

Kamlesh Kumar Bhutani,  Professor and HeadDepartment of Natural Products and Dean, NIPER India.

Drug discovery from natural products has reclaimed the attention of the pharma industry and is on the verge of a comeback due to new technological inputs that promise better returns on investment.

Natural products, particularly, microbial and plant products in their native form have been associated with mankind since ancient times. These have played a vital role in the discovery of New Chemical Entities (NCEs) in the golden period (1981-2002) of drug discovery. Drugs derived from natural sources also served as drug leads suitable for optimisation by synthetic means.

The old laborious processes involved in the extraction and isolation were not capable of generating the numbers which were required to keep pace with the High Throughput Screening (HTS) requirements. Further, advancement in the knowledge of molecular mechanisms, cellular biology and genomics not only increased the number of molecular targets but also demanded shorter drug discovery timelines. The advent of newer combinatorial techniques of synthesis and computational methods, with the incongruity of natural products to keep pace with the ever growing competition for novel classes of drugs at a faster rate, has prompted pharmaceutical industries to look towards synthetic chemical libraries. Though pharmaceutical industry appreciates the role of nature as the chief architect of natural products' libraries and respect the science therein, they fear carrying out research in the area. It is unfortunate that discovery for the industry means custom synthesis of "me-too" kind of molecules instead of novel and therapeutically superior molecules from nature. However, the rethinking on fresh strategies popularly known as "natural product redux" is on the verge of gaining prominence due to disappointing results of combinatorial chemistry and high throughput screening in delivering potent chemical entities.

Combinatorial chemistry generates larger libraries but the compounds therein are relatively simple planar molecules contrary to the natural products' pool that gives a much higher hit-rate in high throughput screening with high chemical diversity. Further, improvements in isolation, purification and characterisation procedures have fastened the output of natural product research, thereby reviving the interest of the pharmaceutical industry.

The modern natural product research is undergoing a revolution due to recent advancements in combinatorial biosynthesis, microbial genomics and screening processes. The resourcing of properly authenticated higher terrestrial plants has become easier due to monographs generated by Indian Council for Medical Research (ICMR) and the Department of Ayurveda Yoga Unani Siddha Homeopathy (AYUSH). Moreover, access to hyphenated techniques like Liquid Chromatography-Mass Spectrometry, Liquid Chromatography-Nuclear Magnetic Resonance have raised the hope of drastically reducing the time and cost involved in natural product research by using dereplication processes that are combination of techniques to avoid the already reported compounds.

The unique molecular diversity of natural compounds can be leveraged in the design of combinatorial libraries to improve their inherent biological activity or drug-like properties. This can be performed by semi-synthetic modification of the parent molecule or by fully synthetic methods after crucial structural elements required for biological activity are defined from the libraries and refined by computer-assisted drug designing methods. In comparison to the past, more specific targets, efficient in vitro as well as in vivo models are available and can be utilised. Current strategies in natural product research involve a multifaceted approach combining botanical, phytochemicals, biological and molecular techniques.

In a paradigm shift from discovery of single bioactive molecules, multi-constituent mainstay of bioactive extracts can be emphasised for synergistic and antagonistic studies at cellular and molecular levels. Of the 250,000 species of higher terrestrial plants in existence, only 5 to 15 percent are estimated to have been chemically and pharmacologically investigated in systematic fashion. India has a repository of 45,000 different plant species, out of which around 15,000 are medicinal plants. 1.5 million practitioners of the Indian system of medicine use around 10 percent of the medicinal plants for preventive, primitive and curative applications.

Natural Products in Drug Discovery
Today, the perceivable threat of extinction of biodiversity due to global warming and other environmental reasons is also very high. Thus, there is an urgent need to identify the indigenous natural resources to study them in detail for use in drug discovery. Moreover, sustainable supply of medicinal plants is essential for practising traditional medicine as well as natural product drug discovery. About 70 percent of the supply of herbal raw material for the Ayurveda, Siddha, Unani and homoeopathic medicines comes from the wild. There is enormous scope for India, with its rich biodiversity, to contribute to this trade. To enhance this, it is important that the cultivation programmes of the medicinal plants be carried out using controlled and scientific methods so that these will ensure plant material of desired quality and also help manage the resources effectively. However, the growing demand for medicinal plants is also threatening their existence. For meeting the future needs, cultivation of medicinal plants has to be encouraged.

The pharmaceutical industry has to come forward in utilising the knowledge available in traditional medicines like Ayurveda. Traditional medicines may provide cure for different types of diseases and disorders but need scientific validation. In order to focus the research on traditional medicines to serve national interests, the first priority is to assess the therapeutic quality of herbal medicines objectively since the dividing line between the modern therapies and traditional therapies remains imprecise.

The assessment of quality can be made easier if distinction is drawn between rational and empirical medication taking into account marked psychodynamic effects associated not only with the active substances, but also with their typical indications. It is satisfying to note that companies such as Ranbaxy, Lupin and Nicholas Piramal India Ltd. (NPIL) have started their efforts for using the traditional knowledge in the development of their formulations as well as in drug discovery programmes. The formulations that will be manufactured in these companies use Good Manufacturing Practices and Best Quality Practices to ensure standardised, safe and effective herbs as well as finished phytomedicines that can be made popular like the Chinese medicines all over the world. Ranbaxy has setup its new herbal centre for the development of herbal medicine at Gurgaon, while the NPIL's research centre is located at Mumbai and Lupin's at Pune.

The therapeutic areas of inflammation, metabolic diseases and obesity may receive more attention for the development of natural products. Inflammation process is considered to be the root cause of almost all the diseases including cancer at the molecular level. Lifestyle diseases like obesity and metabolic disorders are silent killers which have gone unnoticed so far. A huge amount of information is already available in traditional medicine about their cures. Many plants and their secondary metabolites have already been researched for these areas and the pharmaceutical industry should take steps in utilising this valuable information.

The Road Ahead

An integrative approach by combining the various discovery tools and the new discipline of integrative biology will provide the key for success in natural product drug discovery and development. Natural products can be predicted to remain an essential component in the search and development for new, safe and economical medicaments. Pharmaceutical industry must awaken to change its mindset and reorient its resources towards the natural product-based drug discovery programs.

An integrative approach by combining the various discovery tools and the new discipline of integrative biology will provide the key for success in natural product drug discovery and development.

Author Bio

Kamlesh Kumar Bhutani