Steps of drug development (cont'd...)
Various ways to find out a lead
a. Pharmacophore development (by high throughput screening)
This is an abstract description of molecular features which is necessary for molecular recognition by a biological macromolecule. The development of a pharmacophore is done by computer based drug design (computational chemistry)
or quantitative structure based drug design (Q-SAR). In computer based rug design computer simulation of the existing drug is done, adding or removing different chemical groups on it. Few molecules are screened by the simulation, which are only taken to the next step of drug development. On the other hand, in Q-SAR, new molecules are synthesized in the lab, adding or removing different chemical group on the existing drug and it is evaluated for the therapeutic effect. The structure of the target is important to determine the structure of the pharmacophore by Q-SAR method [Kier LB, 1971].
b. Reverse pharmacology
This is a very promising way to find a lead, where the development of a new drug, based on it's traditional use is studies under this branch of pharmacology by trans-disciplinary exploratory studies (in vitro and in vivo) [Ashok DBV, 2014].
Examples: Turmeric is applied on the area of bleeding after cutting by a knife. Based on this use, Curcuma longa (turmeric) was tested for antibacterial activity on 1949. After that Curcumin is isolated from curcuma longa and further evaluated and now successfully used as anti-inflammatory, hypoglycemic, antioxidant, wound-healing, and antimicrobial agents [Subash CG et. al., 2013]. There are many other examples which are evaluated for multiple medicinal activities based on their traditional uses (eg. Azadirachta indica, Allium sativum, many more to name).
These are the agents, developed from the biological sources and the method to develop the biopharmaceuticals is called biotechnology. Hormones, erythropoietin, growth factors etc. are the examples of biopharmaceuticals. It is solely dependent on the pathology of the disease. As for example, the insulin was discovered, when it was established that the absence of the $/beta$ cells of islets of Langerhans impairs the carbohydrate digestion. The researchers engaged to find out the molecule, secreted from $/beta$ cells and they become successful [Rang MP et. al., 2007].
v. Lead optimization
All the lead molecules screened are not accepted for further studies. In this step of drug discovery, the leads are tested for target specificity (the property of the molecule to selectively bind with the target of our interest), metabolic stability (the chemical nature of the molecule to be stable enough in physiological system), oral absorption (the capability of the molecule to move to the extracellular fluid from the site of administration) and obvious adverse reactions. If the molecule passes in the screening it is allowed to send in the pre clinical study [Rang MP et. al., 2007].
[Ashok DBV, 2014] Ashok DBV, Reverse Pharmacology-A Paradigm Shift for Drug Discovery and Development, Current Research in Drug Discovery, vol. 1, issue 2, 39-44, 2014.
[Kier LB, 1971] Kier LB, Molecular orbital theory in drug research, Academic Press, 164-169, 1971.
[Rang MP et. al., 2007] Rang HP, Dale MM, Ritter J M, Moore P K, Pharmacology, 5th Edition, Elsevier, 2-752, 2007.