In recent years, there is a quest for searching novel molecules to eradicate the diseases all around the world; however development of academia and industries in India towards drug discovery and development is a big question. In order to make progress in institutions and industries en route for drug discovery, our researchers need to update the knowledge on recent advances in drug discovery and development. Advanced methods such as semi-synthetic modifications of natural products by computational techniques fragment based screening and combinatorial technology in medicinal chemistry, homology modeling and virtual high-throughput screening in bioinformatics and use of in-vitro methods alternatives to animal studies in pharmacological and toxicological studies can be incorporated with traditional Indian way of research to attain the goal. We must be more innovative and try to hybridize various ideas and have a system of culture which allows more experimentation rather than stick to old failed ideas and systems. With our history of over 10,000 years of civilization, abundance of natural herbal therapeutic repertoire and the knowledge we have gained through Vedas on Ayurvedic Medicine which works on systems and organs, rather than receptors, we try to blend the ideas of traditional with advanced scientific technologies in drug discovery and development to discover the new molecules.
India has been on the receiving end in terms of drug discovery and development with the inherent fear and apprehension that it cost more and it takes lot of time to develop a drug and bring them to the market. Not many of us have questioned or even tried to think of developing alternative paradigm in drug discovery rather than stick to the conventional target or receptor theory which we are all trained to think. With our history of over 10,000 years of civilization, abundance of natural herbal therapeutic repertoire and the knowledge we have gained through Vedas on ayurvedic medicine which works on systems and organs, rather than receptors, we have not paid any attention to them. Let me hasten to add, none of us should be bound either to the allopathic or ayurvedic system of medicine, rather we should take advantage of both or even better establish new and hybrid systems yet to be identified to come up with better, faster and cheaper therapeutic preparations for the masses.
The initial task in drug research is to identify new lead compounds with desired biological activities. These can be obtained by chemically modifying known drugs or by isolating novel natural chemicals from living organisms, especially plants. Bioassay-based fractionation can be used to isolate and identify novel compounds from such botanical sources. They can then be further isolated and characterized.
I. Natural herbal therapeutic products
Originating from the two Sanskrit words, ayus (life) and veda (science), Ayurveda is an ancient healing system originating in the Indian subcontinent that relies on herbs for maintaining good health. Historical records suggest that the journey of Ayurveda began in India more than 5,000 years ago, and this traditional system of healing has influenced both Unani human therapy conceptualized by Hippocrates and ancient Chinese remedies. Thus, use of plants and plant based products in treating health conditions hails back to human history and forms the origin of many modern medicines. Herbal sources are generally considered non-toxic, easily affordable and locally available. Even today, more than 70% of the world's population depends on plant-based remedies to meet their health care needs. Many conventional and effective drugs originated from plant sources, for example, aspirin (willow bark), digoxin (from foxglove), quinine (from cinchona bark), and morphine (from the opium poppy). However, the advent of industrial revolution triggered the rise of allopathic medicines, which changed both the perspective and enthusiasm of practitioners towards herbal medicines.
Indian traditional medicine system loaded with evidence based on usage of alternative medicine (Herbal medicine) could come forward in presenting to Western scientist the efficacy of herbs or its formulation coupled with some life style modification in treating some of the chronic conditions for which current allopathic system only works in controlling the symptoms. However, it should be noted that the typical ways in which modern medicine is studied in clinics may not be applicable to the alternative system, hence, it needs to be studied in an environment which is reproducible yet scientifically convincing enough.
First of all, herbal products have the ability to act at different locations, in a concerted manner to produce an effect, which is very different from the way the synthetic molecules act. Conventional medicines are usually oriented to act on a single target, with a higher intensity that disturbs the network between the signaling pathways. As a result, the equilibrium inside the cells is disturbed. Homeostasis is retained with natural products because the effect is moderate and spread over different signaling pathways at a single time point. The overall impact has therapeutic relevance without the accompanying adverse events that are common with synthetic molecules. Thus, herbal extracts heal a pathological state moderately, in a holistic fashion, without disturbing the cellular homeostasis.
Secondly, herbal formulations often combine several different herbs, considering the principles of synergy and buffering that helps to improve efficacy of the formulation and reduce adverse effects. This is in contrast to conventional practice, where polypharmacy is generally avoided, owing to high risk of adverse drug-drug interactions.
Finally, practice of herbal medicines involves use of different diagnostic principles, thus rendering adoption of a multimodal treatment approach against a pathological condition. For example, treatment of arthritis surrounds observations of patient's elimination pattern also, as arthritis possibly results from "an accumulation of metabolic waste products". Based on this, a combination of herbs with diuretic, cholerectic or laxative actions are prescribed alongside herbs with anti-inflammatory properties. The mode of treatment adopted under conventional pharmacy, however, incorporates only a unidirectional approach instead of a holisticone.
Thus, we should adopt holistic approach where all the existing system of disease treatment are utilised. For acute conditions, allopathy works better and for chronic conditions including age related diseases ayurvedic system works better. Hence, instead of depending upon one, the hybrid system can be a more viable option. Another advantage of holistic approach could be in studying the effect under scientific conditions. The efficacy of treatment using conventional medicine and the one supplemented with ayurvedic system could be easytoanalyse.
Unfortunately, there are few Indian industrial companies that are exploring new molecules from natural sources. Most of them are restricting their focus on herbal formulations whereas the enormous cost involved in isolation of pure compounds from plants is perhaps the prohibitive factor. Luckily, efficacy of herbs and their different formulations have been studied extensively by a few Indian companies which have come up with herbal formulations for several acute and chronic diseases with wide acceptance among common masses along with scientifically trained doctors following western medicines. Thus, it could be a way to reach out to outside world with potential benefits associated with traditional form of medicine.
Natural products (NPs) remain a prolific source for the discovery of new drugs and drug leads even from Vedic period. Recent data suggests that 80% of drug molecules are natural products or natural compound inspired. The rich biodiversity of India has remained untouched as far as discovery of new chemical entities is concerned. The world community has realized the importance of Indian medicinal system, consequently the global demand for natural products in the form of neutraceuticals, dietary supplements and functional foods is growing up all over the world, which is good sign for Indian herbal industry. NPs, besides being source of leads for a number of drugs, also plays an important role in the industrial synthesis. This is because of the presence of a wide chemical diversity in natural products, which enables them to be starting materials for several stereo-specific reactions. In addition, there is desperate attempt to produce the library of com pounds on NPs(BhutaniandGohil, 2010).
NPs are typically secondary metabolites, produced by organisms in response to external stimuli such as nutritional changes, infection and competition. NPs produced by plants, fungi, bacteria, protozoans, insects and animals have been isolated as biologically active pharmacophores. Approximately one-third of the top-selling drugs in the World are NPs or their derivatives. Moreover, NPs are widely recognized in the pharmaceutical industry for their broad structural diversity as well as their wide range of pharmacological activities (Strohl,2000).
On the other hand, limitations to the wider therapeutic use of these NPs are: limited supply of the drugs from the natural sources, low yields, lack of Good Manufacturing Practices and quality controls, slow growth and sparsely distribution of the species, and commercially not viable total synthetic methods. It is therefore essential to explore the alternative approaches and also to understand the biosynthesis of natural products. Natural products not only served as drugs to treat various human ailments, they also played a very important role as template to develop synthetic drugs. As a result, focus has shifted on biotechnology tools, genetic engineering and synthetic biology to produce the bioactive compounds from engineered microorganisms (Narender,2012).
About screening of NPs, the decision when to screen NP extracts compared to compound libraries is extremely important for the successful integration of NPhits into a lead discovery program. This is because no matter how quickly the active compounds can be isolated and their structures identified, there will always be a lag time behind the evaluation of pure compounds whose structure and method of synthesis is known at the onset. In fact, screening of NP extracts well before a synthetic library would be preferable, but in practice this rarely, if ever, happens. Alternatively, NP extracts may be used asa last resort when no lead series have been identified after completion of all other screening. While in principle this seems attractive, the screening of these types of drug targets must not be overdone, as using NPs only for difficult targets unfairly biases its output compared to other techniques. Therefore, screening NP libraries against various types of drug targets in a way complementary to compound libraries offers the most efficient way of discovering a new drug lead. Beside all these approaches, semi-synthetic modifications by using computational techniques can also be tried for the existing hits to get the better lead compounds from the natural products (Butler, 2004 and Bhutani and Gohil,2010).
II. Medicinal Chemistry
In the current milieu, medicinal chemists who are engaged in drug discovery and development areas are part of interdisciplinary teams, and must therefore be prepared to understand not only the field of organic chemistry, but the range of other disciplines to anticipate challenges and interpret developments to help move the project forward. The role of medicinal chemist has changed significantly in the past century. In the early era of drug discovery (1950-1980), medicinal chemists relied primarily on data from in-vivo testing. In the more recent period, the development of new technologies and new tools such as High-Throughput in-vitro screening, large compound libraries, combinatorial technology; defined molecular targets, fragment based lead screening, click chemistry, peptidomimetics, natural products based drug design, diversity oriented synthesis, chemogenomics, virtual screening, transition-metal-catalyzed carbon-carbon bond forming reactions and high-field NMR and preparative HPLC, has changed the paradigm of drug discovery.
Although, these new technologies present many opportunities to the medicinal chemist, the multitude of new safety requirements that have arisen has also brought unanticipated hurdles for the task of translating in-vitro activity into in-vivo activity. Nowadays, the rapidly expanding knowledge based concerning disease, their causes, symptoms and their effects on the human body holds great promise for the discovery of important new medicines (Lombardino and Lowe 111,2004).
With the help of molecular biology in combination with computer assisted drug design, medicinal chemists can now rationally design new drug molecules with known targets in mind. These compounds would have computational data, encouraging the intended results even before they screen. This saves time and allows for a more comprehensive understanding of the drug-target interplay (Patil, 2012)
However, success in this arena still requires skilled medicinal chemists making correct choices, often with insight gleaned from interactions with computational chemists and structural biologists, about which hits are likely to play out as true lead structures that will meet the plethora of hurdles that any drug candidate must surmount. The chemists also need to be conversant with issues of toxicology, given the primary cause of failure of drug candidates in early development continues to be preclinical toxicology. Although, the potential for genotoxicity can be assessed directly through a number of in-vitro assays, the same does not hold true for end-organ toxicities (such as drug induced liver damage) or immune mediated toxicities. The recent advances discussed above have put more tools in the chemist's toolkit, but in order to use these tools effectively, it invariably comes down to the ability to make the absolutely "correct" molecule in a timely and cost-effective manner (MacCoss&Baillie,2004).
Indian medicinal chemistry has the sophistication and where with all to meet this challenge, however, complementary biological support is sorely lacking in India.
III. IT and bioinformatics
Bioinformatics is a science in which biology, computer science, and information technology merge into a single discipline. The ultimate goal of the field is to enable the discovery of new biological insights as well as to create a global perspective from which unifying principles in biology can be discerned. There are three important sub- disciplines within bioinformatics: the development of new algorithms and statistics with which to assess relationships among members of large data sets; the analysis and interpretation of various types of data including nucleotide and amino acid sequences, protein domains, and protein structures; and the development and implementation of tools that enable efficient access and management of different types of information (Wishart, 2005).
Bioinformatics is a set of enabling technologies responsible for the annotation, storage, analysis and retrieval of nucleic acid sequence, protein sequence and structural information.
Bioinformatics is being applied to speed up the drug discovery process by moving towards data-driven drug discovery, to improve efficiency, trim down costs and the timeliness and provide wider access to the entire life sciences sector (Madhan, 2003). The completion of the human genome (Venter et al., 2001) and, more recently, the completion of the mouse, rat, and dog genomes (Gibbs et al., 2004; Parker et al., 2004; Waterston, 2002), are already having a significant impact on our understanding of drug metabolism and drug toxicity. Likewise, the application of standard genomics/proteomics technologies, such as gene chips, mass spectrometry, 2D gels, or NMR spectrometry, is now allowing much more rapid and thorough characterization of the absorption, distribution, metabolism, excretion (ADME) and toxicity (T) of potential drug leads (Ackermann et al., 2002; Kassel, 2004). Not only are these computational techniques having an impact on the early phases of drug discovery, but so too are they having an impact further down the developmental pipeline.
Bioinformatics has proven indispensable to drug discovery and development process to solve the cost and time woes of the pharmaceutical industry. It has significant advantages over traditionally expensive and time consuming "wetlab" research methods, because computational tools give the most predictive and accurate information about genes and proteins with regards to mediating aspects of drug action. Following bioinformatics tools are available for Indian scientists for this work:
1. Virtual High-Throughput Screening (vHTS)
2. Sequence Analysis
3. Homology Modelling
4. Similarity Searches
5. Drug Lead Optimization
6. Physicochemical Modelling
7. Drug Bioavailabilityand Bioactivity
Bioinformatics with rapid advances in gene, protein, and drug identification will lead to swift, sharp reductions in both the time and cost of drug discovery (Figure 1). Tangible proof that the bioinformatics revolution will economize drug discovery is emerging. India with high IT infrastructure, educated and experienced staff will be a formidable competitive force in bioinformatics and boon to drug development globally.
In the future, we can expect that the scope of predictive or analytical methods in drug metabolism and ADMET will grow, and so too will the score or breadth of information contained in many bioinformatics or che mi-informatic databases. It is not unreasonable to expect that in the near future, data will be collected on human physiological, genetic, metabolic, and even epidemiological information. Perhaps this epidemiological information will incorporate characteristics of specific disease populations and racial or ethnic groups. This information could then be integrated with high-throughput in vitro ADMET data to predict the population distribution and likelihood of various ADRs, toxic effects, or pharmacokinetic parameters. This kind of in-silico clinical trial work is already starting to happen in a few small companies and academic consortia (www.simcyp.com). Given the rapid pace of development in bioinformatics, we can only expect to be continuously surprised by the power of the computer and the innovative ideas coming from the people who program them.
IV. Use of In Vitro Alternative Methods
Over the last30-years there has been an increasing realization that the biomedical community is using animals where some of the In vitro tests can be employed as a first attempt. There has been a continuous effort to find alternative approaches which avoid testing on animals wherever possible (Gibbs, 2008). In the last 15-years or so, numerous In Vitro tests have been developed and validated by various regulatory agency participation and NGO groups, in addition to Industry involvement. As of this writing, tests for skin corrosion, eye irritation, dermal absorption, skin sensitization have been fully validated hence; there is no apparent need for any acute testing for these end points. Indian Biomedical scientists can easily take upon this challenge at very minimal expense and develop new and innovative In vitro tests which can bring down the cost of drug discovery and development and more importantly can reduce the use of animals and cut down the time lines for drug development. Cell culture technologies form the basis of most alternative methods. They have matured over the last decades but severe limitations still remain (Hartung, 2007). The critical question is how well the cell in culture reflects the cell in the organism, especially with regard to its state of differentiation and its response patterns in isolation in an artificial environment. Differentiation can be seen as the cellular equivalent of the phenotype at the level of an organism. Hence, there is a need of formal sense for standardized tests or a quality assurance process for the In Vitro models in research and cell based screening approaches.
Another step Indian government can take is to revise the Schedule Y guidelines to eliminate unnecessary animal testing which no other governments need or require, in particular rat and rabbit testing for biosimilars, among others. In fact, Schedule Y is totally silent on In Vitro toxicity or cell based tests in preclinical safety testing. We realize that toxicity testing in animal models cannot reveal all potential toxicity in humans. However, even studies in human subjects, such as in phase I or phase II clinical trials, are unable to reveal all potential adverse effects in humans because of limited number of subjects involved. It is important to bear in mind when developing alternatives that the ultimate goal is prediction of health effects in humans, and there is thus a need to change the mind-set from trying to mimic animal data and one-to-one replacement for each target organ. One of the major challenges is to reproduce integrated responses. There is a need to develop approaches/strategies for combining and interpreting data on multiple targets/end points, obtained from a variety of alternative methods, so that they can be used in human risk assessment (Kelleretal., 2009).
Large scale exploitation of In Vitro tests is an area which is totally unexplored and Indian scientific community can easily undertake which can give a moral boost to the global drug development community to take advantage of Indian technology at a nominal cost and reduce the drug development cycle and bring new and innovative drugs to the market at an affordable cost.
V. Clinical Trials in India
Approximately $40 billion is spent annually on drug development which constitutes nearly 70 per cent of drug development expenses are incurred in clinical testing. Such costs could be reduced to half when clinical research activities are outsourced to low cost economies such as India. There are at any point in time over 500 molecules undergoing clinical trials in various phases in a large number of centres around the World. In contrast to the drug discovery process, the clinical development process is heavily dependent on the human element; hence, regions of the world with cost competitive human resources are an attractive alternative. With nearly one billion people as potential patients and a large number of highly skilled investigators, India clearly falls into this category. India has a competitive advantages in clinical trials based on favourable regulators climate, English language proficiency of doctors, staff of hospital, clinical analysts thereby collapsing the time needed for the clinical development process and investigators, large pool of treatment naive patients, high speed of subject recruitment and low cost of clinical studies India provides a large pool of "treatment-naive patients" who hail from multi-ethnic and multi-racial backgrounds. In spite of these advantages, bulk of the existing so called Medical CRO's that are in India have not reached global standards of ethics and technological automation that is called for in these studies. Major investments in medical infrastructure and training in clinical pharmacology in various therapeutic areas is in order.
However, foreign companies stop clinical trials in India after government amends rules on compensation. The new regulations-Drugs and Cosmetics (First Amendment) Rules, 2013- for clinical trials has some problematic clauses, according to the researchers. One clause states that for an injury/illness, occurring to a clinical trial subject, he or she shall be given free medical management as long as required. This does not specify what type or cause of injury, Thus, a trial participant may be involved in a traffic accident or assaulted by someone, but under the open-ended clause, the trial sponsor has to cover all costs. This is unreasonable.. Therefore, constantly changing government regulation is a big hurdle although good intent but difficult to implement.
In summary, we have provided a few easily targetable arrows which Indian scientists can use and may offer some advantages in future drug development. There can never be a single path that offers all the solutions. We are optimistic that Indian talent, with some favourable changes in regulatory guidelines and moderation of business climate, our scientists can and will play a pivotal role in drug development.
(Authors are working with Syngene International Limited, Bangalore)
(Courtesy:Indian Analytical Instruments Association)