title: Benzo[e]pyrimido[5,4-b][1,4]diazepin-6(11H)-one derivatives as Aurora A kinase inhibitors: LQTA-QSAR analysis and detailed systematic validation of the developed model.
abstract: Aurora kinases are sub-divided into Aurora A, Aurora B, and Aurora C kinases that are considered as prospective targets for a new class of anticancer drugs. In this work, a 4-D-QSAR model using an LQTA-QSAR approach with previously reported 31 derivatives of benzo[e]pyrimido[5,4 -b][1,4]diazepin -6(11H)-one as potent Aurora kinase A inhibitors has been created. Instead of single conformation, the conformational ensemble profile generated for each ligand by using trajectories and topology information retrieved from molecular dynamics simulations from GROMACS package were aligned and used for the calculation of intermolecular interaction energies at each grid point. The descriptors generated on the basis of these Coulomb and Lennard-Jones potentials as independent variables were used to perform a PLS analysis using biological activity as dependent variable. A good predictive model was generated with nine field descriptors and five latent variables. The model showed [Formula: see text]; [Formula: see text] and [Formula: see text]. This model was further validated systematically by using different validation parameters. This 4D-QSAR model gave valuable information to recognize features essential to adapt and develop novel potential Aurora kinase inhibitors.
authors.affiliation: Pharmacy Department, Faculty of Technology & Engineering, The Maharaja Sayajirao University of Baroda, Kalabhavan, Vadodara, Gujarat, 390001, India.
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Kanhed
authors.affiliation: Visiting Research Associate to Pharmacy Department, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Radha Charan
authors.initials: RC
authors.lastname: Dash
authors.affiliation: Department of Mathematics, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Nishant
authors.initials: N
authors.lastname: Parmar
authors.affiliation: Department of Mathematics, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Tarun Kumar
authors.initials: TK
authors.lastname: Das
authors.affiliation: Pharmacy Department, Faculty of Technology & Engineering, The Maharaja Sayajirao University of Baroda, Kalabhavan, Vadodara, Gujarat, 390001, India.
authors.forename: Rajani
authors.initials: R
authors.lastname: Giridhar
authors.affiliation: Pharmacy Department, Faculty of Technology & Engineering, The Maharaja Sayajirao University of Baroda, Kalabhavan, Vadodara, Gujarat, 390001, India. mryadav11@yahoo.co.in.
authors.forename: Mange Ram
authors.initials: MR
authors.lastname: Yadav
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D064096:Aurora Kinase A
keywords: 4D-QSAR; Aurora A kinase; Cancer; Conformational ensemble profile; Molecular dynamics