Pharmacophore modelling

Activity prediction is based on a list of models (i.e., QSAR models, pharmacophore models, etc.) that are maintained on the server. There is a second level of access so that only authorized users may be allowed to add or delete model entries. 

The align/pharmacophore experiment orients the molecules to obtain maximum similarity in chemical features. This application can then generate a pharmacophore model consistent with all the molecules. 

Risperidone (11) was also included among a a 1-adrenergic receptor antagonists to study a quantitative structure-activity relationship (99BMC2437). A pharmacophore model for atypical antipsychotics, including 11, was established (00MI41). An increased plasma level of 11 and 9-hydroxyrisperidone (12) was observed in combination with paroxetine (01 MI 13). The effect of vanlafaxine on the pharmacokinetics of 11 was reported (99MI13). 

Zhang J, Yu K, Zhu W, Jiang H (2006) Neuraminidase pharmacophore model derived from diverse classes of inhibitors. Bioorg Med Chem Lett 16 3009-3014 Ziircher T, Yates PJ, Daly J, Sahasrabudhe A, Walters M, Dash L, Tisdale M, McKimm-Breschkin JL (2006) Mutations conferring zanamivir resistance in human influenza virus N2 neuraminidases compromise virus fitness and are not stably maintained in vitro. J Antimicrob Chemother 58 723-732... 

Muscarinic M3 Receptor. A pharmacophore model was derived from known M3 receptor antagonists, using the program DISCO, and 3D searching was performed by Unity 3D in the Astra Charnwood in-house compound repository and the databases of several commercial suppliers. The 172 compounds that fitted the pharmacophore were screened for their M3-antagonistic potency. Several compounds with micromolar and even submicromolar activities resulted, for example, compound 13 (A50 M3 antagonism 0.2pM pA2 = 6.67 Fig. 16.2) [85],... 

Flohr S, Kurz M, Kostenis E, Brkovich A, Fournier A, Klabunde T. Identification of nonpeptidic urotensin II receptor antagonists by virtual screening based on a pharmacophore model derived from structure-activity relationships and nuclear magnetic resonance studies on urotensin II. J Med Ghent 2002 45 1799-805. 

Li H, Sutter J, Hoffmann R. HypoGen an automated system for generating 3D predictive pharmacophore models. In Gtiner OF, editor. Pharmacophore perception, development and use in drug design., La Jolla International University Line, 2000. p. 173-89. 

Egnell AC, Houston JB, Boyer CS. Predictive models of CYP3A4 heteroactivation in vitro—in vivo scaling and pharmacophore modelling. J Pharmacol Exp Ther 2005 312 926-37. 

Smith PA, Sorich M, McKinnon R, Miners JO. QSAR and pharmacophore modelling approaches for the prediction of UDP-glucuronosyltransferase substrate selectivity and binding. Pharmacologist 2002 44 supplement. 

Figure 20.2 Pharmacophore models for P-gp inhibition. A. P-gp inhibition pharmacophore aligned with the potent inhibitor LY335979. B. P-gp substrate pharmacophore aligned with verapamil. C. P-gp inhibition pharmacophore 2 aligned with LY335979. Green indicates H-bond acceptor feature, and cyan indicates hydrophobic feature. See color plate.

Pajeva IK and Wiese M. Pharmacophore model of drugs involved in P-glycoprotein multidrug resistance explanation of structural variety (hypothesis). J Med Chem 2002 45 5671-5686. 

D QSAR pharmacophore model for the ileal Na /bile acid cotransporter. J Lipid Res 1999 40 2158-68. 

Chang C, Pang KS, Swaan PW, Ekins S. Comparative pharmacophore modeling of organic anion transporting polypeptides a meta-analysis of rat Oatplal and human OATPIBI. J Pharmacol Exp Ther 2005 314 533-41. 

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