Receptor-Based Pharmacophore

From the previous chapters, it is known that a pharmacophore is the group of features that is essential for the biological activity of a molecule and we have discussed it in the context of analogue or ligand-based virtual screening [40], We can also build a pharmacophore query in the absence of ligands based only on the receptor information which is known as receptor-based pharmacophore modelling [41], 

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Usually, this is known as dynamic receptor-based pharmacophore as the pharmacophore is generated by considering the dynamic (different conformations) nature of the protein [42], 

In the third step (negative image sampling), the chemical features in the active site are known by molecular interaction field analysis and identification of excluded volumes [43]. It has its appheation in designing novel inhibitors in the drug discovery field [44], 

5 Active Site-Directed Pose Prediction Programs for Efficient. 

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Receptor-based pharmacophore Pharmacophore hypotheses generated from the 3D structure of the receptor... 

Ligand-Based and Receptor-Based Pharmacophore Modeling and QSAR Analysis... 

Most receptor-based pharmacophore models have been developed by using one crystal, NMR, or model structure. Pharmacophore models based on a single receptor structure could fail to identify inhibitors that bind to structures that are somewhat different from the experimental or model structure but that are still readily accessible at physiological temperatures. To address this issue, Carlson et al. (58-60) developed a dynamic pharmacophore model in which a number of... 

The inclusion of the protein active site can add an important steric or shape constraint to the search, limiting the size of the selected molecules appropriately, as shown by application to the thyroid hormone receptor [75]. However, the real power of such methods comes from the ability to search receptor-based pharmacophores with only a limited user bias on the points to be used. This has been implemented via partial-match searching [103], available within UNITY, which marks a molecule as a hit if it matches 4 out of 20 possible pharmacophoric features in the site. Additional constraints on the solutions can be imposed by grouping the pharmacophore points and limiting matches to one or more points from each group, a feature of the THINK program [78]. In this way, molecules can be selected that explore several areas of the binding site. 

Venkatachalam, C.M., Kirchoff P., and Waldman, M. (2000) Receptor-based pharmacophore perception and modeling, in Pharmacophore Perception, Development and Use in Drug Design (ed O.F. Guener), lUL Biotechnology Series, lUL, La Jolla, CA, pp. 339-350. 

Tervo et al. [155] described a successful virtual screening experiment for the class III histone deacylase sirtuin type 2 (SIRT2). Using two databases of commercially available compounds plus a receptor-based pharmacophore query, 4 out of 11 tested molecules showed weak to moderate inhibitory activity. The two most active inhibitors vdth IC50 values of 51 and 91 pM had new scaffolds (Figure 12.14b). 

Wermuth CG, Ganellin CR, Lindberg P, Mitscher LA (1998) Glossary of terms used in medicinal chemistry (lUPAC Recommendations 1998) Pure Appl Chem 70 (5) 1129-1143 Chen J, Lai L (2006) Pocket v.2 further developments on receptor-based pharmacophore modeling. J Chem Inf Model 46(6) 2684-2691... 

Deng J, Lee KW, Sanchez T, Cui M, Neamati N, Briggs JM (2005) Dynamic receptor-based pharmacophore model development and its application in designing novel HIV-1 integrase inhibitors. J Med Chem 48(5) 1496-1505... 

This article investigates some of these scenarios in greater detail, and presents some newer approaches to 3D searching, including receptor-based pharmacophores and 3D shape analysis and searching. 

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