Structure drug design

Key Words NMR binding studies solution structure drug design binding mode screening binding site. 

After approaches to the solution of the major tasks in chemoinformatics have thus been outlined, these methods are put to work in specific applications. Some of these apphcations, such as structure elucidation on the basis of spectral information, reaction prediction, computer-assisted synthesis design or drug design, are presented in Chapter 10. 

The molecular surface of receptor site regions cannot be derived from the structure infoi mation of the molecule, bth represents the form ofthe active site of a protein surrounded by a ligand. This surface representation is employed in drug design in order to illustrate the volume of the pocket region or the molecular interaction layers [186. ... 

To understand the recommendations for structure descriptors in order to be able to apply them in QSAR or drug design in conjunction with statistical methods or machine learning techniques. 

Following the similar structure - similar property principle", high-ranked structures in a similarity search are likely to have similar physicochemical and biological properties to those of the target structure. Accordingly, similarity searches play a pivotal role in database searches related to drug design. Some frequently used distance and similarity measures are illustrated in Section 8.2.1. 

Depending on the information available about the protein structure and the ligands binding to a particular target, four different cases can be distinguished in drug design, as listed in Table 10.4-2. 

The lead discovery process is depicted in Figure 10.4-4 and shows how the different methods are interconnected. A lead structure can be discovered by serendipity. In rational drug design all information available about a target serves to direct... 

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... 

Nowadays a broad range of methods is available in the field of chemoinfor-matics. These methods will have a growing impact on drug design. In particular, the discovery of new lead structures and their optimization will profit by virtual saeening [17, 66, 100-103]. The huge amounts of data produced by HTS and combinatorial chemistry enforce the use of database and data mining techniques. 

The utility of a protein model depends upon the use to which it is put. In some cases, on< only interested in the general fold that the protein adopts and so a relatively low-resoluti structure is acceptable. For other applications, such as drug design, the model must be me more accurate, including the loops and side chains. In such cases, a poor model may often fa r worse than no model at all, as it can be seriously misleading. 

Kubinyi H1998. Structure-based Design of Enzyme Inhibitors and Receptor Ligands. Current Opinion i. Drug Discovery and Development 1 5-15. 

Kuntz I D 1992. Structure-Based Strategies for Drug Design and Discovery. Science 257 1078-1082. 

E Johansson and M Cocchi 1993. PLS - Partial Least-squares Projections to Latent Structures. In binyi H (Editor) 3D QSAR in Drug Design. Leiden, ESCOM, pp. 523-550. 

There are now extensive databases of molecular structures and properties. There are some research efforts, such as drug design, in which it is desirable to hnd all molecules that are very similai to a molecule which has the desired property. Thus, there are now techniques for searching large databases of structures to hnd compounds with the highest molecular similarity. This results in hnding a collection of known structures that are most similar to a specihc compound. 

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