Structure-Based Drug-Design

The application of protein structures to suggest bioisosteric replacements will be covered more fully in Chapter 10. 

Structure-Based Drug Design (or Structure-Aided Drug Design) 

however, pertinent to state here that an adequate and intuitive user interface exclusively relies upon the inherent ability to produce, modify, and modulate effectively a good number of absolutely independent objects, for instance ligand, and its target. 

The automation of structure-based design can be divided into key areas for development  

The affinity of the designed drug molecule for its site is governed by the free energy of interaction AG. AG can be determined experimentally from the equation 

Where Kb is the experimental binding constant, R is the gas constant and T is the temperature. The free energy has an enthalpic and entropic component. 

Where AH is the change in enthalpy on binding and AS is the change in entropy. 

The success of structure-based design methods in assisting drug discovery efforts has prompted a large number of research efforts towards the issues of docking 

Other innovations in de novo design are provided by Leach et who try to 

Aldose reductase X-ray (1.8 A) 3D-database search + docking Lead discovered 

CDKT Homology model MD Lead optimised in very few iterations 

An overview of docking programs is given in Tabic 10.4-3. Depending on the way the conformational flexibility of the ligand is treated, docking can be either rigid or flexible. 

Recently Schneider and Bolim reviewed programs for dc novo design [66. A list of these is compiled in Table 10.4-4. 

Method Ligand jfexibiUty sampling Scoring function 

Dock [59] incremental build force field or contact score 

Fred (Openeye Software) conformational ensembles Gaussian or empirical score 

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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),...

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. 

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

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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. 

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