A comparative QSAR analysis of substituted imidazolones derivatives as angiotensin II AT1 receptor antagonists

Mukesh C. Sharma1
1School of Pharmacy, Devi Ahilya University, Indore, India

Tóm tắt

Two-dimensional (2D), Three-dimensional (3D) quantitative structure–activity relationship (QSAR) and Pharmacophore studies of angiotensin II AT1 receptor antagonists substituted imidazolones derivatives have been carried out. Statistically significant best 2D-QSAR and k-nearest neighbor-based 3D-QSAR model were generated on q 2 = 0.7118; 0.7159 with pred_r 2 = 0.8313, 0.7377, respectively, was developed by genetic algorithm-PLS techniques. The pharmacophore model generated consisting of the five-point hypotheses contains two HAc (hydrogen bond acceptor) site, one negative ionizable and two AroC feature (aromatic) region. On the basis of generated models, a statistically valid 2D and 3D-QSAR with good predictability was developed. All molecular modeling studies were compared to each other. The current study may help in designing novel Angiotensin II AT1 receptor.

Tài liệu tham khảo

Ajmani S, Jadhav K, Kulkarni SA (2006) Three-Dimensional QSAR using the k-Nearest Neighbor method and its interpretation. J Chem Inf Model 46:24–31 Baumann K (2002) An alignment-independent versatile structure descriptor for QSAR and QSPR based on the distribution of molecular features. J Chem Inf Comput Sci 42:26–35 Bernhart CA, Perreaut PM, Ferrari BP, Muneaux YA, Assens Jean-Louis A, Clement J, Haudricourt F, Muneaux CF, Taillades JE, Marie-A Vignal, Gougat J, Guiraudou PR, Lacour CA, Roccon A, Cazaubon CF, Jean-C Brelihre, Le Fur G, Nisato DA (1993) New Series of Imidazolones: highly Specific and Potent Nonpeptide AT1 Angiotensin II Receptor Antagonists. J Med Chem 36:3311–3380 Clark M, Cramer RD III, Van ON (1989) Validation of the general purpose tripos 5.2 force field. J Comput Chem 10:982–1012 Cramer RD III, Bunce JD, Patterson DE (1988) Cross validation, bootstrapping, and partial least squares compared with multiple regression in conventional QSAR studies. Quant Struct Act Relat 7:18–25 De Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T (2000) International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 52:415–472 Golbraikh A, Tropsha A (2002) Predictive QSAR modeling based on diversity sampling of experimental datasets for the training and test set selection. J Comput Aided Mol Des 16:357–369 Halgren TA (1996) Merck molecular force field. III. Molecular geometries and vibrational frequencies for MMFF94. J Comput Chem 17:553–586 Israili ZH (2000) Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. J Hum Hypertens 14(Suppl. 1):S73–S86 Johnston CI (1992) Renin-angiotensin system: a dual tissue and hormonal system for cardiovascular control. J Hypertens 10:S13–S26 Klebe G, Abraham U, Mietzner T (1994) Molecular similarity indices in a comparative analysis (COMSIA) of drug molecules to correlate and predict their biological activity. J Med Chem 37:24–30 Li YP, Weng X, Ning FX, Ou JB, Hou JQ, Luo HB, Li D, Huang ZS, Huang SL, Gu LQ (2013) 3D-QSAR stud-ies of azaoxoisoaporphine, oxoaporphine, and oxoisoaporphine derivatives asanti-AChE and anti-AD agents by the CoMFA method. J Mol Graph Model 41:61–67 Menard J, Bouhnik J, Clauser E, Richoux JP, Corval O (1983) Biochemistry and regulation of angiotensinogen. Clin Exp Hypertens A 5:1005–1019 Moorthy NSHN, Ramos MJ (2011) Fernandes PA (2011) Structural analysis of α-glucosidase inhibitors by validated QSAR models using topological and hydrophobicity based descriptors. Chem Intel Lab Sys 109:101–112 Nahmias C, Strosberg AD (1995) The angiotensin AT2 receptor searching for signal-transduction pathways and physiological function. Trends Pharmacol Sci 16:223–225 Politi A, Durdagi S, Moutevelis-Minakakis P, Kokotos G, Papadopoulos MG, Mavromoustakos T (2009) Application of 3D QSAR CoMFA/CoMSIA and in silico docking studies on novel renin inhibitors against cardiovascular diseases. Eur J Med Chem 44:3703–3711 Richon AB (1997) Young SS an introduction to QSAR methodology. Netw Sci Corp, Saluda Stoll M, Unger T (2001) Angiotensin and its AT2 receptor: new insights into an old system. Regul Pept 99:175–182 Todeschini R, Consonni V, Gramatica P (2009) Chemometrics in QSAR. Comprehen-sive Chemometrics. Chem Biochem Data Ana 4:129–172 Vallotton MB (1987) The Renin-Angiotensin System. Trends Pharmacol Sci 8:69 VLife MDS 3.5 (2008) Molecular design suite. Vlife Sciences Technologies Pvt. Ltd., Pune