Pharmacophore development

Bremner, J.B., Coban, B. and Griffith, R. (1996) Pharmacophore development for antagonists at alpha 1 adrenergic receptor subtypes. Journal of Computer-Aided Molecular Design, 10, 545-557. 

In order to develop small molecules capable of eliciting similar effects as AFC in the pharmacologic inhibition of Icmt, it has thus become evident that specific structural requirements must be observed. Specifically, the isoprenyl motif was identified as a necessary recognition group and the presence of a correct prenyl moiety is a key feature for biological activity. Thus, pharmacophore development for Icmt inhibitors became the focus of several research groups in the coming years. 

Filizola M, Villar HO, Foew GH (2001) Differentiation of 5, p, and K opioid receptor agonists based on pharmacophore development and computed physicochemical properties. J Comput Aided Mol Des 15 297-307... 

FIGURE 28.7 Molecular structures of hH3R antagonists used for the pharmacophore development. 

Prior to the discovery of the cannahinoid CBi receptor, CB SARs were developed by those who hypothesized that at least some of the effects produced by CBs may be receptor mediated. The early SAR that emerged has been reviewed comprehensively by Razdan (1986) and by Makriyannis and Rapaka 1990). These reviews consider both classical and non-classical CB compounds. Because there is struc-tural/conformational similarity between the classical and non-classical CBs (Lagu et al. 1995 Reggio et al. 1993 Xie et al. 1994,1996,1998), unified pharmacophores developed for these two classes have agreed with one another and have led to a consensus pharmacophore that involves the existence of the following at the CBi receptor ... 

Lee, KW. and Briggs, J.M. (2001) Comparative molecular field analysis (CoMFA) study of epofhilones—tubulin depolymerization inhibitors pharmacophore development using 3D QSAR methods./. Comput. Aid. Mol. Des., 15, 41—55. 

Hit selection First-round SAR studies Pharmacophore development 2nd to wth round of SAR Pharmacokinetics and pharmacodynamics Mechanistic studies... 

This section is not intended to provide an in-depth gnide to the development of pharmacophore models, bnt we hope that the benefit of including this type of analysis is self-evident. There are many excellent guides and pnblications on this subject available in the literature [11-13]. The basic steps performed for pharmacophore development are as follows ... 

Keller PA, Bowman M, Dang KH, Garner J, Leach SP, Smith R, McCluskey A. Pharmacophore development for corticotrophin-releasing hormone new insights into inhibitor activity. J Med Chem 1999 42 2351-2357. 

This alert describes a smicrure-based pharmacophore developed primarily om compounds that have been reported to be moderate or strong inhibitors of the HERG (human eiher-a-go-go rdated gene) potassium funnel [Pearlstein et aJ, Cavalli et al. Ekins et alj... 

Pharmacophore development and SAR studies of imidazoline receptor ligands 12MRM1542. 

The classic approach to pharmacophore development has been through the visual analysis of low-energy ligand conformer superpositions using molecular modeling packages. The work undertaken by Bures et al. to design new inhibitors of auxin transport provides an excellent example of the use of... 

A number of alternative 3D QSAR techniques have been advanced that also show potential in the area of pharmacophore development. Good et al. have developed a technique that utilizes molecular similarity matrices to derive... 

Figure 2 Screen from Catalyst displaying a hit retrieved from the Maybridge database based on an angiotensin II blocker pharmacophore developed by Peter Sprague. The conformation of the hit with the highest score is shown overlaid with the original query...

Figure S Screen from Catalyst displaying an angiotensin II blocker pharmacophore developed by Erich Vorpagel using Apex-3D and translated into ISIS query format (top), A hit, the angiotensin inhibitor Zolasartan from Derwent s World Drug Index database, retrieved with this topology-based 3D query (bottom)...

D searching and pharmacophore development. They have been extended by the addition of lipophilicity to the standard steric and electrostatic field descriptors. Another 3D QSAR technique which can be used in conjunction with 3D searching is molecular shape analysis (MSA). Use of the genetic function algorithm within a molecular field analy.sis (MFA) has also been demonstrated to be a useful alternative to CoMFA and MSA. These approaches depend on proper superposition of the structures that are being compared. This... 

In this chapter, rather than discussing the components of in silico modeling we highlight three recent research approaches, (1) molecular overlay, (2) ANN modeling, and (3) pharmacophore development, focusing on specific sets of arthropod repellents. 

---