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Once the structures and conformations of molecules are known, they can be overlapped, compared, and visualized in ways only possible using computers and computer graphics (often called molecular graphics). A number of programs are widely available that perform these tasks. Differences in shape can often be related to differences in how molecules bind to regulatory proteins such as enzymes and receptors. Often such analysis is augmented by consideration of molecules' electric fields or other properties. In this way, a 3-dimensional hypothesis of the binding requirements of a particular protein can be developed. When joined with multivariate analysis, a 3-dimensional QSAR equation can be derived from the molecular models of a series of molecules and their known biological activities, similar to the relationships, mentioned above, derived for molecular properties [5]. |
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The methods discussed above deal solely with the drug molecules, themselves. Recent advances in the methods of protein structure determination have allowed another course of action, structure-based (often called rational) drug design (SBDD) [1620]. In this approach, drug discovery is guided by knowledge of the biochemical pathways that one hopes to alter using drugs. Usually, this means understanding, at the atomic level, the structure and function of a particular protein, such as an enzyme or else a hormone receptor. The goal is to alter the protein's function, either by making it work better, or usually by inhibiting its function. Enzymes catalyze a transformation of substrate molecules; hormones attach themselves to receptors that signal their presence. Both types of proteins have binding sites for the hormones or substrates. Through SBDD techniques, drugs are designed through direct investigation of the protein and binding site in an effort to determine the optimal structural, electrostatic, and hydrogen-bonding interactions that will make for a good fit. For example, in order to replicate, the AIDS virus requires the proper functioning of the enzyme, HIV-protease, which cleaves a particular viral protein, its substrate. Much effort in anti-AIDS drug development has targeted this protein with the goal to develop molecules that fit into the binding site and prevent the enzyme from binding and cleaving its substrate [21]. |
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Structure-based drug development relies heavily on the experimental fields of protein x-ray crystallography and protein nuclear magnetic resonance (NMR) to provide the atomic-level structures of the proteins. However, computational methods play important roles in the derivation of the structure from the raw data. Some are unique to the processing of the crystallographic or NMR data. However, molecular graphics, molecular mechanics, and molecular dynamics methods are heavily used to refine the solution to provide the final experimental model. |
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Unfortunately, often an experimentally determined structure of the desired protein is not available. The experimental approaches can be involved and often time consuming, sometimes requiring months or even years to determine |
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