Based Drug Design

In the absence of useful three-dimensional information about the site, the designer can only build novel molecular structures based on molecular similarity with existing active molecules. Ligand-based design requires the resolution of a number of technical issues. These are itemized below. 

A set of molecules is needed to extract spatially distributed chemical features for inclusion in drug design. 

Structurally dissimilar, active molecules provide more information about the site than a series of active close structural homologs. 

The molecules in the initial ligand set may have numerous torsion angles making identification of the active conformation difficult. 

The choice of molecular similarity procedure needs to be made from a wide variety of available methods, preferably including one that includes a search for partial molecular similarity. This allows a more useful set of similarities to be identified. 

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Colman, 1994] Colman, P. Strncture-based drug design. Curr. Opinion Struct. Biol. 4 (1994) 868-874... 

Thus there is a distinction between ligand- and structure-based drug design, which are described in more detail in Sections 10.4.6.1 and 10.4.6.2. 

Figure 10.4-5. Different strategies to design a ligand in structure-based drug design docking (left), building (center), and linking (right),...

Distinguishing Molecules of Different Biol< ical Activities and Finding a New Lead Structure - An Example of Ligand-Based Drug Design... 

In general the relevance of predictions of structure-function relationships based on molecular modeling and structural bioinformatics are threefold. First they can be used to answer the question of which partners (proteins) could interact. Second, predictions generate new hypotheses about binding site, about molecular mechanisms of activation and interaction between two partners, and can lead to new ideas for pharmacological intervention. The third aim is to use the predictions for structure-based drug design. 

X-Ray Crystallographic Analysis and Structure-Based Drug Design. 32... 

Also in the 1980s, structure-based drug design (SBDD) underwent a similar cycle. Early proponents oversold what could be achieved through SBDD, thereby causing pharmaceutical companies to reconsider their investments when they discovered that SBDD too was no panacea for filling the drug discovery cornucopia with choice molecules for development. Nevertheless, SBDD was an important advance. 

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Veerapandian P, editor. Structure-based drug design. New York Marcel Dekker, 1997. 

Bohacek RS, McMartin C, Guida WC. The art and practice of structure-based drug design a molecular modeling perspective. Med Res Rev 1996 16 3-50. 

Kubinyi H. Combinatorial and computational approaches in structure-based drug design. Curr Opin Drug Discov Dev 1998 1 16-27. 

Rutenber E, Fauman EB, Keenan RJ, Ortiz de Montellano PR, Meng E, Kuntz ID, DeCamp DL, Salto R, Rose JR, Craik CS, Stroud RM. Structure of a nonpeptide inhibitor complexed with HIV-1 protease. Developing a cycle of structure-based drug design. J Biol Chem 1993 268 15343-6... 

Gschwend DA, Sirawaraporn W, Santi DV, Kuntz ID. Specificity in structure-based drug design identification of a novel, selective inhibitor of Pneumocystis carinii dihydrofolate reductase. Proteins Struct Funct Genet 1997 29 59-67. 

Raevsky, 0. A. Physicochemical descriptors in property-based drug design. Minirev. Med. Chem. 2004, 4, 1041-1052. 

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