AIDS success

Successes of Computer Aided Drug and Agrochemical Design

Computer aided chemical design (CADD) began to be adopted in the pharmaceutical and agrochemical industries in the late 1970’s – early 80’s. In the last 25 years these techniques have become so widely accepted that every research based company of a reasonable size in these industries has a dedicated CADD group. The earliest success stories involved a method known as Quantitative Structure-Activity Relationships (QSAR) in which mathematical models are constructed between a biological response and a quantitative description of chemical structure. Fujita (1) reported at a conference in 1984 the optimization of the herbicidal lead structure shown to the right.
The activity (pI₅₀ ) of analogues of this compound could be related to hydrophobicity (p) and size (E_s ) by the equation shown to the right.
Another CADD technique which complements QSAR is Structure Based Drug Design (SBDD) which makes use of the X-ray structure of biological targets such as enzymes and pharmacological receptors. A recent article on the impact of structure guided drug design (2) lists over 40 compounds discovered with the aid of SBDD which have entered clinical trials. At the time of writing of that article (August 2003) seven of the compounds had become approved and marketed drugs.
Perhaps the most dramatic illustration of the success of SBDD is seen in this graph from the Centre for Disease Control (copied with thanks from www.nigms.nih.gov/news/facts/structure/drugs.html ). AIDS deaths dropped sharply in 1995, when HIV protease inhibitors became available to patients.
(1) T. Fujita, in: QSAR and Strategies in the Design of Bioactive Compounds, J. K. Seydel, Ed., VCH, Weinheim, 1985, pp 207-218.
(2) L.W. Hardy & L. Milikayil, Curr. Drug Discovery, December 2003, pp 15-20.