Purushottamachar Puranik - First chemical feature-based pharmacophore modeling of potent retinoidal retinoic acid metabolism blocking agents (RAMBAs): identification of novel RAMBA scaffolds

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      Publication Details (including relevant citation   information):

      Eur   J Med Chem. 2012 Jan;47(1):412-23. Epub 2011 Nov 17.


      The first three-dimensional (3D) pharmacophore model was   developed for potent retinoidal retinoic acid metabolism blocking   agents (RAMBAs) with IC(50) values ranging from 0.0009 to 5.84nM.   The seven common chemical features in these RAMBAs as deduced by   the Catalyst/HipHop program include five hydrophobic groups   (hydrophobes), and two hydrogen bond acceptors. Using the   pharmacophore model as a 3D search query against NCI and   Maybridge conformational Catalyst formatted databases; we   retrieved several compounds with different structures (scaffolds)   as hits. Twenty-one retrieved hits were tested for RAMBA activity   at 100nM concentration. The most potent of these compounds,   NCI10308597 and HTS01914 showed inhibitory potencies less (54.7%   and 53.2%, respectively, at 100nM) than those of our best   previously reported RAMBAs VN/12-1 and VN/14-1 (90% and 86%,   respectively, at 100nM). Docking studies using a CYP26A1 homology   model revealed that our most potent RAMBAs showed similar binding   to the one observed for a series of RAMBAs reported previously by   others. Our data shows the potential of our pharmacophore model   in identifying structurally diverse and potent RAMBAs. Further   refinement of the model and searches of other robust databases is   currently in progress with a view to identifying and optimizing   new leads.

      Address (URL): http://www.ncbi.nlm.nih.gov/pubmed/22130607