A paradigm for development of novel PTP 1B inhibitors: Pharmacophore modelling, atom-based 3D-QSAR and docking studies

作者：Malla Priyanka; Kumar Rajnish; Mattewal Samiya Kaur; Mahapatra Manoj Kumar; Kumar Manoj

来源：Medicinal Chemistry Research, 2014, 23(2): 927-938.

DOI：10.1007/s00044-013-0690-5

• Docking
• MM-GBSA
• Pharmacokinetic
• Pharmacophore
• T2DM

Inhibitors of protein tyrosine phosphatase 1B (PTP 1B) are of great interest for the development of newer therapeutics for the management of type 2 diabetes mellitus (T2DM). In order to understand structural requirement of molecules to act as PTP 1B inhibitors, ligand-based pharmacophore model, atom-based 3D-QSAR and structure-based drug design studies have been performed on a series of thiophene derivatives to correlate their molecular architecture with PTP 1B inhibitory activity. A five-point pharmacophore hypothesis with one hydrogen acceptor (A), two negative ionic (N), and two aromatic rings (R) as pharmacophoric features were developed using PHASE module of Schrodinger suite. The pharmacophore hypothesis was characterized by good PLS statistics (survival score = 3.894, the best cross validated r(2) (Q(2)) = 0.737, regression coefficient r(2) = 0.968, Pearson-R = 0.887 and F value = 253.3). Docking studies demonstrated binding orientations of ligands in dataset with bidentate binding pockets of the enzyme and importance of hydrophobic groups. Taken together, Partial least square (PLS) generated 3D-QSAR pharmacophore and regression cubes along with structure based drug design provided a three dimensional topological view of active site that can be used for rational modification of ligands for optimal PTP 1B inhibitory activity.

• 出版日期2014-2