Design structure-based

A recent successful application of these methods was the work at Roche on DNA gyrase [146]. The LUDI maps for this site are shown in Fig. 4.6. Pharmacophores derived from these maps were used to search the corporate database using LUDI and Catalyst. Structures were deliberately chosen to be of low molecular weight and were screened at high concentration, so-called needle screening. The subsequent actives were then further developed via structure-based design techniques and medicinal chemistry to give several different series of active compounds. 

A green dot indicates a bit is turned on (pharmacophore is present in the molecule). (Reprinted with permission from [149]). 

However, further extrapolation of this result is premature. Changes in template substitution and differing interactions between kinases have been shown to affect the binding orientation of kinase inhibitor templates [43, 112). 

One of the greatest challenges associated with application of S B D to all discovery processes is the production of protein and subsequent crystallization, particularly when the protein itself is membrane-bound. Many validated fungicidal targets unfortunately fall into the membrane-bound group and this has inhibited the 

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Structure-based Design Methods to Design HiV-1 Protease Inhibitors... 

Structure-based Design of Templates for Zeolite Synthesis... 

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

EK Kick, DC Roe, AG Skillman, G Lm, TJ Ewing, Y Sun, ID Kuntz, lA Ellman. Structure-based design and combinatorial chemistry yield low nanomolar inhibitors of cathepsm D. Chem Biol 4(4) 297-307, 1997. 

Pande V, Ramos MJ (2005) NF-kappaB in human diseases current inhibitors and prospects for de novo structure-based design of inhibitors. Curr Med Chem 12 357-374... 

Nelfinavir. Using structure-based design in conjunction with predicted oral pharmacokinetics, NFV was identified and found to have potent inhibition of HIV-1 in vitro with an IC50 in the 2nM range (Kaldor et al. 1997). Clinical trials of NFV revealed robust and sustained reductions in HIV-1 RNA with over half of all subjects attaining a persistent 1.6 logxo reduction at 12 months, in conjunction with a mean increase in CD4 cells of 180-200 per mm (Markowitz et al. 1998). In subjects... 

The inhibitory activity of furanosyl nonulosonic acid derivative 32, and its structure with N9 sialidase, served as a starting point for the structure-based design of... 

Chan T-H, Xin Y-C, von Itzstein M (1997) Synthesis of phosphonic add analogs of siaUc acids (Neu5Ac and KDN) as potential sialidase inhibitors. J Org Chem 62 3500-3504 Chand P, Kotian PL, Dehghani A, El-Kattan Y, Lin T-H, Hutchison TL, Babu YS, Bantia S, Elliott AJ, Montgomery JA (2001) Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity. J Med Chem 44 4379 392... 

Stoll V, Stewart KD, Mating CJ, Muchmore S, Giranda V, Gu Y-GY, Wang G, Chen Y, Sun M, Zhao C, Kennedy AL, Madigan DL, Xu Y, Saldivar A, Kati W, Laver G, Sowin T, Sham HL, Greer J, Kempf D (2003) Influenza neuraminidase inhibitors structure-based design of a novel inhibitor series. Biochemistry 42 718-727... 

There are three main contributions that structural methods are making to the drug discovery process—structural biology, structure-based design, and structure-based discovery. 

In this chapter, we briefly review various aspects of the chemical information systems used by the chemist for literature and patent searches the field of computer-aided drug design technologies, cheminformatics, as well as other applications. We place special emphases on the ligand-based techniques and only briefly mention the structure-based design technologies. 

Historically, ligand structure-based design has been the most widely used approach to the design of target-directed chemical libraries. Methods that start from hits or leads are among the most diverse, ranging from 2D substructure search and similarity-based techniques to analysis of 3D pharmacophores and molecular interaction fields (Fig. 15.2). 

TABLE 15.1 Specialized Computational Technologies for Target Structure-Based Design of Combinatorial Libraries... 

Tondi D, Costi MR Enhancing the drug discovery process by integration of structure-based design and combinatorial synthesis. In Viswanadhan AK, Chose VN, editors. Combinatorial library design and evaluation. New York Marcel Dekker, 2001. p. 563-604. 

Figure 16.1 Some success stories of structure-based design.

Kubinyi H. Structure-based design of enzyme inhibitors and receptor ligands. Curr Opin Drug Discov Dev 1998 1 4-15. 

DesJarlais RL, Seibel GL, Kuntz ID, Furth PS, Alvarez JC, Ortiz de Montellano PR, DeCamp DL, Babd LM, Craik CS. Structure-based design of nonpeptide inhibitors specific for the human immunodeficiency virus 1 protease. Proc Natl Acad Sci USA 1990 87 6644-8. 

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