The term ‘drug discovery’ refers to the process of discovering new therapeutic candidates. New drugs are continuously required to treat diseases that cannot be managed successfully with existing treatment and to improve the outcome of current treatment (such as safety, potency, tolerability and convenience). Thus, drug discovery caters to the unmet medical demands and thus helps to improve the global health status. However, drug discovery is a complex procedure that is usually lengthy (often extending beyond a decade of continuous efforts), expensive, and has risks of failure. For example, development of drugs related to the central nervous system takes more time (about 10 to 15 years) compared to other classes of drugs.
Historically, drug discovery was mostly limited to the identification of active ingredients in traditional remedies and crude extracts of medicinal plants. The discovery of morphine from opium is one such example. Accidental and unplanned drug discoveries such as penicillin have also been reported. Drug discovery methods have gradually evolved ever since with improvement in technology.
With the advancement in synthetic techniques, chemical libraries of molecules could be generated. These synthesised molecules were randomly screened for their therapeutic potency without the knowledge of the biological target. Such attempts at drug discovery had high risks of failure. Only after identifying a potential therapeutic candidate, attempts were made to identify and study the target involved. This classical pharmacology approach is based on the understanding that the effects of a drug arise out of specific interactions with biomolecules within the body. The classical pharmacology approach of drug discovery replaced the need for screening of crude extracts with purified chemicals and contributed to the beginning of the modern pharmacology era.
Gradually, with an improved understanding of the molecular pathways involved in a disease, small molecules could be designed to specifically target the pathway. Simultaneously, with rapid cloning techniques, large quantities of purified proteins could be produced. The proteins and target-specific molecules synthesised are screened against specific biological targets. This approach, also known as the reverse pharmacology approach is relatively simpler compared to classical pharmacology and avoids the need to screen a large number of extracts and chemical libraries of molecules. Currently, reverse pharmacology approach i.e., target-based drug discovery is extensively used.
Once the screening hits are identified, medicinal chemistry and molecular modelling studies help to optimise the screening hits in terms of their potency, safety, metabolic stability, and bioavailability. Once a successful hit satisfying these criteria is obtained, drug development procedures are continued and clinical trials are conducted. Attempts are usually made to identify more than one successful hit since most molecules face challenges at different drug developmental stages and do not progress till the end of the drug development process. In fact, it is estimated that 1 out of 8 molecules designed is successfully developed and marketed as a drug.
Modern drug discovery process depends upon the identification of a biological target such as a receptor, gene, enzyme, etc. that is rationalised to be involved in the molecular pathway underlying a disease. Thus, drug discovery and development requires close coordination between chemistry, biology, pharmacokinetics, and toxicology. Identification of a biological target drives the drug discovery process. However, even if the target is validated, the candidate drug will only be useful if it interacts with the target in the desired way and is physiologically well-tolerated. Furthermore, the candidate drug needs to have appropriate pharmacokinetic properties, so that the relationship between the drug dosage and its action can be determined. These are some of the objectives of the preclinical and clinical trials undertaken as a part of the drug development process.
With the advancement in medicinal chemistry and molecular modelling, the number of potential drug candidates reaching the clinical trial stages has reduced significantly. During 1991, potential drug candidates with unsuitable pharmacokinetic properties led to 40% drug development failures, whereas, by 2000, this significantly reduced to less than 10%.
Chris Lipinski’s ‘‘rule of five’’ provides a simple approach to drug design based on the physicochemical and structural properties of successful drug molecules. They are:
(i) The candidate molecule should not have more than five hydrogen bond donor atoms/centres.
(ii) The candidate molecule should not have more than ten hydrogen bond acceptor atoms/centres.
(iii) The molecular weight of the candidate molecule should be less than 500 Da for linear molecules.
(iv) logP should be less than 5, where ‘P’ refers to the partition coefficient of the candidate molecule.
Chris Lipinski’s rule is known as ‘‘rule of five’’ since all the rules involve parameters that are equal to 5 or multiples of 5.
The developed drug candidate needs to be approved by regulatory authorities prior to their marketing. To achieve regulatory approval, sound scientific evidence needs to be provided along with cross-validation of studies to support the drug action and its mechanism, pharmacokinetics, drug efficacy, and toxicity. Therefore, it is important to determine at the drug development stage whether the candidate drug has the potential to meet the regulatory requirements. Regulatory approval for the drug as investigational new drug application (INDA) can be requested upon successful completion of preclinical trials or upon the successful completion of the clinical trials as a new drug application (NDA). Once the drug is approved, it can be commercially manufactured adhering to strict and high standard protocols approved by the drug regulatory authorities.
Investment in drug discovery is often determined by the financial viability of investment in the particular drug candidate/biological target. Drug discovery and development attract investment despite the risk of failure, due to the immense prospect of a successful therapeutic candidate in terms of fulfilling the unmet need for therapy especially in diseases such as cancer and Alzheimer’s disease, and the potential financial return.