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Computer-aided drug design becomes a field unto itself partly through the application of these varied computational chemistry techniques to pharmaceutical discovery problems. However, since each method has the potential to provide a piece of the puzzle that provides the route to a new pharmaceutical, equally important to the definition of this field is the coordination of these diverse areas of expertise to maximize the synergy among them as well as between them and experimental methods. The CADD specialist must know what methods to apply, the reliability of the answers, and how those answers fit into the overall drug discovery process. Overall, the expectation is one of decreased time and effort spent in drug discovery. |
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An appreciation of the depth and breadth of the field and its cross-disciplinary nature can be obtained from several recent overviews and reviews [18]. |
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III. What Information Does CADD Provide? |
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Some of these techniques are used to predict the atomic-level structure and conformation (3-dimensional arrangement of atoms) of molecules both small (less than several hundred atoms) or large (thousands to hundreds-of-thousands of atoms as in biological molecules, such as proteins). Others are used to calculate a wide range of properties of these molecules, including reactivity, size, and solubility. Once obtained, structure-activity or structure-property relationship approaches find relationships between these structures and properties and either biological activities of the molecules or yet other properties. Rational drug-design is based on knowledge of the structure and mechanism of key regulatory proteins. The methods of protein secondary and tertiary structure prediction as well as molecular modeling and simulation assist in obtaining this information. Once protein structure is known, molecular docking and potential-energy function analysis help to evaluate the interaction and action of drug candidates and aid in planning further compound synthesis. De novo design helps to discover drug candidates from a consideration of only the protein structure. The overall goal in this work is to provide information to the discovery program that will accelerate the determination of the atomic structure of a new therapeutic agent. |
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In a real sense, much of CADD can be considered to be an outgrowth and extension of the thought processes used by medicinal chemists, who in fact developed many of the approaches. The earliest applications of CADD assisted medicinal chemists in understanding those physical and structural features of molecules that contributed to their biological activity. By understanding these |
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