The drug discovery as perceived is a process by which new drugs are discovered. The development of drug discovery field is a key to a blooming health sector and thus ensures a healthy life. In this review we cover various aspects of the efforts that go into the process of developing a new drug.

Pharmaceutical industry in India today is more poised to do research that is an outcome through collaborations. The drug discovery is a process by which new candidates of drug molecules are discovered. Previously drugs were discovered through identifying the actives from traditional remedies or by serendipity. Drug discovery is a very time consuming and a costly process. Today some of the pharmaceutical industry research is focusing more on the diseases which fall short of treatment due to lack of specific drugs. With the rising number of infectious disease and an increase in the aging population there is an urgent need to find new targets and to get a drug that has a potential to give an optimum time of therapy and is potent enough to kill the cause. Currently a lot of research is being carried in the fields of diabetes, cardiovascular diseases, cancer, tuberculosis and some on the neglected diseases. Since the time the process of drug discovery was recognized till today it has undergone a paradigm shift from serendipity to a more rational way of process.

Drug designing approaches
The drugs generally are not discovered as such, but a more likely the lead compound is discovered. The lead is an idealized molecule, which is modified and optimised to remove the unwanted properties to give a potential compound with optimum desired activity, to give a compound worthy to undergo the various phases in clinical trials. Once a compound that fulfils all of these requirements has been identified, it will begin the process of drug development prior to clinical trials. There are very few drugs known to be developed without a lead, to name them are Penicillin V and Librium. Once they were identified they were taken as the leads and this gave rise to classes of Penicillins and Diazepams respectively. Number of ways for identification of a lead are used which include random and targeted screening, drug metabolism studies, clinical observations and the rational approach. Rational approach involves the design of a compound of a particular activity. The classical pharmacology, forward pharmacology, or phenotypic drug discovery is a method in which the phenotypic screening of whole organism or intact cells of chemical libraries of synthetic small molecules, natural products or extracts to identify substances that have a desirable bioactive effect. The chemical libraries of synthetic small molecules, natural products or extracts were screened to identify substances that have a desirable therapeutic effect in a process known as classical pharmacology.

Modern day drug discovery includes the CADD (Computer Aided Drug Discovery) which makes use of various softwares from Accelerys, FlexX, Schrodinger, VLife, etc. The computational approach involves identification of screening hits, medicinal chemistry and optimization of those hits to increase the efficacy, affinity, selectivity (reduction of lethal of side effects), stability (to increase the half-life), and oral bioavailability. One or more of steps in drug development may, but not necessarily, involve computer-aided drug design. The advances in techniques of X-Ray crystallography and NMR have lead to simplification of complex protein structures. This has helped the researchers in identification of target compound.
1.    Structure based drug designing: When the 3D structure of target protein is known the lead identification becomes easier and the active ligand binding site can be studied using molecular modeling techniques. The docking techniques involve use of softwares like DOCK which is a flexible docking method, FlexX, GOLD, AutoDock,etc
2.    Ligand based drug designing : The QSAR uses statistics which correlates biological activity to the structural properties of molecule. Also the pharmacophore is an important concept in rational drug designing, the pharmacophore can be generated based computational softwares and when a lead is known the substructure or similarity search can be carried to get newer efficient drugs.
 
In the field of drug discovery, reverse pharmacology also known as target base drug discovery (TDD), a hypothesis is first made that modulation of the activity of a specific protein target will have beneficial therapeutic effects. Screening of chemical libraries of compounds is then done to identify compounds that bind with high affinity to the target and the hits from these screens are then used as starting points for drug discovery. Post the discovery of genomics this method has caught up speed as rapid cloning and the synthesis of large quantities of purified proteins is possible. Small molecules were synthesized to specifically target a known physiological/pathological pathway. This led to great success, such as the work of Elion and Hitchings on purine metabolism, the work of Black on beta blockers and cimetidine, and the discovery of statins by Akira. One of the mammoth approach of developing chemical analogues of known active substances was  by Sir David Jack  at Allen and Hanbury's (later Glaxo), who pioneered the first inhaled selective beta2-adrenergic agonist and steroid  for asthma, ranitidine as a successor to cimetidine.

 Nature is still an excellent source for the development of new drugs or discovery of compounds serving as precursors to drugs. Amongst the drugs which make to the market a major chunk come from compounds derived from natural origin. Natural product research has been a very successful field for new drug discovery. Unlike the chemical structures derived from combinatorial chemistry the natural product structures exceeds our imagination. The common examples drug compounds isolated from crude extract are morphine, the active agent in opium, and digoxin, a heart stimulant originating from the leaf Digitalis lanata. The natural products isolated from biological sources have also been synthesised with the use of organic chemistry. Unmodified natural products have sometimes succeeded as drugs example paclitaxel. The natural products have served as a lead to many of the established drugs from streptomycin, artemesin, ephedrine etc. The various fields bioinformatics, Chemical information & computing systems, Genetics, Biochemistry, X-ray crystallography, NMR and Mass Spectrometry have contributed immensely in the field of drug discovery.

Various stages of drug discovery
The time taken by a potential drug candidate to reach market is anywhere between 10 to 15 years and the investment of a drug discovery is huge. The process of drug discovery is a highly complex and a multidisciplinary task. The pressure to perform on a medicinal chemist is also immense since the company rides that amount of investment on basis of the employees.
1.    Initiation of the process begins with identification of target is done first then based on the target the hits are identified.
2.    The leads are then optimized and subjected to preclinical testing and the successive clinical trials. On an average of the 1000 drugs that enter preclinical testing only 1 successfully passes the human testing.
3.    The efficacy proof of the concept is shown in the Phases of Clinical trials. After passing the stringent parameters set by the US FDA the drug is launched and a post marketing surveillance is done.
Drug discovery and market: India and the World
“Great drugs build great franchises, but great franchises don’t necessarily build great drugs” - Unknown

Lots of technologies have come and gone in the drug industry, often with the promise of lowering the cost of inventing a medicine. Yet the cost has gone up regardless of the efforts. The average drug developed by a major pharmaceutical company costs at least $4 billion, and it can be as much as $11 billion. US regulators approved 39 new molecular entities (NMEs) in 2012, the most in 16 years, suggesting that pharmaceutical makers are poised for growth after losing huge investments in recent years to generic drug makers because of patent expirations. There were eight approvals in December alone, including a new treatment from Johnson & Johnson called Sirturo for drug-resistant tuberculosis approved on Monday, the first new TB drug in decades. The tally of 39 new drugs and biological products approved by the Food and Drug Administration compares with 30 in 2011 and just 21 in 2010. At least 10 of the drugs had fast track status in 2012, which enabled them to be reviewed more quickly.

In 2013 a total of 27 NMEs were approved of which 9 were First-in-Class Type. First-in-Class, meaning drugs which, for example, use a new and unique mechanism of action for treating a medical condition. First-in-Class is one indicator of the innovative nature of a drug and a 33% First-in-Class approval rate suggests that the group of CY 2013 NMEs is a field of innovative new products. These includes drug like Adempas, Imbruvica, Invokana, Kadcyla, Kynamro, Mekinist, Sovaldi, Tecfidera, Xofigo. Also 33 percent of the NMEs approved in CY 2013 (9 of 27) were approved to treat rare or “orphan” diseases that affect 200,000 or fewer Americans. This is significant because patients with rare diseases often have few or no drug treatment options. Orphan drugs include Adempas, Gazyva, Gilotrif, Imbruvica, Kynamro, Mekinist, Opsumit, Pomalyst,Tafinlar. Hence we can say that 2013 has been a year of strong quality of research in the field of drug discovery. The FDA also lists the NMEs as Fastrack, Breakthrough, Priority Review, Combined, etc.

In 2014 there were 41 new approvals, of which 15 were fast track, 8 were breaktrough, 25 were priority review and 8 were accelerated approval. Akynzeo, Dalvance, Lynparza, Opdivo, Zydelig, Cerdelga, Keytruda, Northera are some of the new entities approved in 2014 by Centre for Drug Evaluation and Reasearch (CDER).  

Drug discovery and bottlenecks
The current Ebola outbreak is the largest and longest ever recorded for the disease, which has a death rate of about 50 percent and has so far killed at least a thousand people, according to the U.N. health agency. It first showed up in Guinea in March and has since spread to Sierra Leone and Liberia, with a suspected cluster in Nigeria. There are several bottlenecks in the process of drug discovery like:

1. The failure of late-stage clinical trials to show efficacy and safety
Drugs are still failing in clinical development because of late toxicity or lack of efficacy. Lack of efficacy and safety are to some extent interrelated: Low dose i.e. high safety but low efficacy and other High dose i.e. high efficacy but low safety
2. High cost, long time of drug development and the late discovery of toxicity leads to the loss of huge investment.

Conclusion
The need of the hour for India is to actively involve great minds to collaborate and work towards giving new and effective drugs at an affordable cost. Prime focus for drug development should be new vaccines, drugs, diagnostics and other products for neglected diseases of the developing world. Also the Indian government should be encouraging the Scientists in the R&D area. The world class technologies can be bought in with a mutual understanding between the two organizations. In recent years India has strengthened the patent laws which are more in compliance with the global practices. Patent process should aim at helping in bringing research and development business. In India a larger section is invested in production than in research activities. Also the closing of the major research and development units of Piramal & AstraZeneca in India is a major blow to the speed in drug discovery. The pace at which the discovery collaborations are being established indicate that Western Pharmaceutical Industry is relying more on India for their brain power and source of innovative research.

(Rakesh R. Somani is Professor and Head of Department, Department of Pharmaceutical Chemistry, VES College of Pharmacy, Mumbai 400 074. Tanvy Pereira is PG Research Student, Department of Pharmaceutical Chemistry, VES College of Pharmacy, Mumbai 400 074)