History of Medicinal Chemistry

The middle third of the  century witnessed a blossoming of pharmaceutical invention, with breakthroughs in the development of synthetic vitamins, hormones (Thyroxine, Oxytocin, Corticosteroids etc.,) anticonvulsant, psychotropics, antihistamines and new vaccines. Several of these constituted entirely new classes of medicines. Illness such as tuberculosis, diphtheria and pneumonia could be treated and cured for the first time in human history. The structures of the steroid hormones were established in the 1930s and 1940s. The discovery of Cortisone as anti-inflammatory agent in 1949 motivated the synthesis of number of anti-inflammatory semi-synthetic steroids such as Prednisolone, Betamethasone, Triamcinolone, Ethynylestradiol and Progestogens. Problems associated with separating the anti-inflammatory activity from the mineralocorticoid activity of the cortical steroids led to interest in the development of non-steroidal anti-inflammatory agents (NSAIDs).

Major innovations were made in cardiovascular drugs starting with antihypertensive and β-blockers in the 1960 s, followed by calcium-channel blockers, ACE inhibitors and cholesterol-reducing drugs. The successes of 1950s and 1960s were leading light by the work of Gertrude Elion and George Hitchings (1988 Nobel Laureates) who introduced Azathioprine, the first immunosuppressive agent, Allopurinol for gout, Acyclovir the first useful antiviral compound against herpes and other DNA viruses.

Early 20^th century also proposed that drugs might elicit therapeutic. and pharmacological actions via interactions with discrete membrane-associated recognition sites, on target organs called receptor turned out as new target in the field of drug research. The pharmacological characterization of receptors in almost all organs, including the brain, provided the basis for a large number of benzodiazepines, β-blockers  γ-amino butyric acid and introduction of monoclonal antibodies, which block receptors of growth on tumor cells. The enhancement of instrumentation and the introduction of powerfúl technology also facilitated laboratory automation and aided the discovery and development of new drugs.

Simultaneous advances in analytical technology viz. detection systems and data capture systems, laboratory automation etc., and in molecular biology viz. in vitro introduction of bioassay design techniques and microplate technology etc., allowed biological targets to be screened that had proven to be intractable before. With all these essential technology ingredients in, place, the pharmaceutical laboratory in the early 1990s was set for the first real version of High Throughput Screening (HTS). HTS is a highly automated robotic system that tests small amounts of large numbers of compounds against potential targets.

In 1990s, when Combinatorial chemistry mushroomed it provides very large numbers of new chemical entities to be screened for biological activity through HTS. It is a novel approach to chemical synthesis that enables the creation of large numbers of organic compounds by linking chemical building blocks in all possible combinations. The objective of both approaches is to provide very large numbers of new chemical entities to be screened for biological activity in vitro. Since the mid-1980s, the geometrical aspects of molecular structures were also taken into account leading to the development of the 3D-QSAR, which exploits information on the molecular geometry.

In spite of the significant advances in biological screening of large number of compounds by using HTS techniques, the screening of many millions of chemicals against hundreds of biological targets are too expensive. Virtual screening of chemical libraries has emerged as a complementary approach to HTS. Molecular graphics added a new dimension to computational chemistry and opened up the field of molecular modeling.