In the early 1990’s there was a great deal of optimism that computer aided drug design would revolutionize the way in which drugs could be developed. The enduring exponential increase in computing power had progressed to the point that rudimentary estimations of ligand receptor complementarity could be performed. Furthermore, computer graphics technology had achieved the ability to generate vector models of chemical structures and manipulate them in real-time. This offered, for the first time, the ability to interactively study computer models of ligand structures and their binding interactions with a receptor.
Concomitant with the development of this technology was the emergence of the AIDS epidemic. During the late 1980s, scientists had isolated the causative agent of AIDS, the HIV-1 virus. Considerable characterization of the viral life cycle provided numerous potential targets for pharmaceutical intervention. Among them was the HIV-1 protease. This aspartyl protease was an enzyme that was unique to HIV, and absolutely required for the processing and maturation of HIV proteins. Thus, if a drug could be developed to inactivate this protease, the virus would be unable to generate mature infectious particles to sustain the infection. Numerous groups around the world rapidly solved the crystal structure of this enzyme (see Figure 1). The mechanism of this enzyme was determined, and the layout of the active site was carefully mapped.
It was known that humans possess similar classes of proteases. Renin is an enzyme secreted by the kidneys that is responsible for initiating a cascade of reactions that regulate blood pressure. It too is an aspartic protease, and ligands that inhibited its function were known. With the wealth of data from the study of the HIV-1 protease, the hope was that this target could be exploited by computer-aided rational drug design to rapidly generate novel AIDS drugs. Computational chemists believed they could circumvent much of the time and effort required for drug synthesis and testing by simply generating novel compounds using the computer. Testing would be replaced by merely calculating the ligand-receptor binding affinity using the physical laws of chemistry. The concept of generating virtual lead compounds entirely through computer simulation was termed denovo design.
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