QSAR and Docking Studies on 1,2-benzisoxazole Derivatives for Antipsychotic activity against Dopamine receptor (D2)
With a view to the rational design of a series of selected 48 substituted benzisoxazoles, 3D-QSAR and docking studies have been performed for the prediction of antipsychotic activity. Overall model classification accuracy was 76.00% (q2 = 0.7600, representing internal validation) in training set and 68.33% (Pred_r2 = 0.6833, representing external validation) in test set using sphere exclusion and forward–backward as a method of data selection and variable selection, respectively. The docking studies suggest that compound 38 interact with GLU43, THR48, GLN79, GLN147, LEU148, ASN149, ASP150, SER151, ARG178, LYS270, LEU273, THR327, GLU43, GLN79, GLN147, ASN149, ASP150, SER151 and GLU43 amino acid residues. Both QSAR and docking study of such derivatives provide guidance for further lead optimization and designing of more potent antipsychotic agents.
2.Potvin S, Pampoulova T, Mancini-Marie A, O. Lipp, Bouchard RH, Stip E. Increased extrapyramidal symptoms in patients with schizophrenia and a comorbid substance use disorder. J. Neurol. Neurosurg. Psychiatry. 2006; 77:796.
3.Wonodi I, Hong LE, Thaker GK. Psychopathological and cognitive cognitive correlates of tardive dyskinesia in patients treated with neuroleptics. Adv. Neurol. (2005) 96:336.
4.Uchida H, Rajji TK, Mulsant BH, Kapur S, Pollock BG, Graff-Guerrero A, Menon M, Mamo DC. D2 receptor blockade by risperidone correlates with attention deficits in late-life schizophrenia. J. Clin. Psychopharmacol. 2009; 29:571.
5.Meltzer HY, Li Z, Kaneda Y, Ichikawa J. Serotonin receptors: their key role in drugs to treat schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2003; 27:1159-1172.
6.Avram S, Berner H, Milac AL, Wolschann P. Quantitative structure–activity relationship studies on membrane receptors inhibition by antipsychotic drugs. Application to schizophrenia treatment. Monatsh Chem. 2008; 139:407.
7.Tehan BG, Lloyd EG, Wong MG. Molecular field analysis of clozapine analogs in the development of a pharmacophore model of antipsychotic drug action. J. Mol. Graph. Model. 2001; 19:417.
8.Strupczewski JT, Bordeau KJ, Chiang Y, Glamkowski EJ, Conway PG, Corbett R, Hartman HB, Szewczak MR, Wilmot CA, Helsley GC. 3-(((Aryloxy)alkyl)piperidinyl)-1,2-benzisoxazoles as D2/5-HT2 antagonists with potential atypical antipsychotic activity: antipsychotic profile of iloperidone (HP 873). J. Med. Chem. 1995; 38(7):1119-1131.
9.VLife MDS 3.5 (2008) Molecular Design Suite, Vlife Sciences Technologies Pvt. Ltd. Pune, India.
10.Halgren TA. Merck Molecular Force Field: I. Basis, Form, Scope, Parameterization and Performance of MMFF94. J. Comp. Chem. 1996; 17:490-519.
11.Metropolis N, Rosenbluth AW, Rosenbluth MN, Teller AH. Equation of state calculations by fast computing machines. J. Chem. Phys. 1953; 21:1087-1092
12.Shen M, Xiao Y, Golbraikh A, Gombar VK, Tropsha A Development and validation of kNN QSPR models for metabolic stability of drug candidates. J. Med. Chem. 2003; 46:3013–3020.
13.Zheng W, Tropsha A. Novel variable selection quantitative structure—property relationship approach based on the k-nearest-neighbor principle. J. Chem. Inf. Comput. Sci. 2000; 40:185-194.
14.Golbraikh A, Tropsha A. QSAR modeling using chirality descriptors derived from molecular topology. J. Chem. Inf. Comput. Sci. 2003; 43:144–154.
15.Ajmani S, Jadhav K, Kulkarni SA. Three-Dimensional QSAR using the k-nearest neighbor method and its interpretation. J. Chem. Inf. Model. 2006; 46:24-31.
16.Sahu NK, Bari SK, Kohli DV. Molecular modeling studies of some substituted chalcone derivatives as cysteine protease inhibitors. Med. Chem. Res. 2012; 21(11):3835-3847.
17.Golbraikh A, Tropsha A. Predictive QSAR modeling based on diversity sampling of experimental datasets for the training and test set selection. J. Comput-Aided Mol. Des. 2002; 16:357-369.
18.Cramer RD, Patterson DE, Bunce JD. Comparative molecular field analysis (CoMFA) 1. Effect of shape on binding of steroids to carrier proteins. J. Am. Chem. Soc. 1998; 110:5959-5967.
19.Parida P, Yadav RNS, Shankar B, Chakraborty D, Das A, Singh NS. In-silico protein ligand interaction study of typical antipsychotic drugs against dopaminergic D2 receptor. Int. J. Pharm. Pharm. Sci. 2013; 5(2):183-189.
20.Nandi S, Bagchi MC. 3D-QSAR and molecular docking studies of 4-anilinoquinazoline derivatives: a rational approach to anticancer drug design. Mol. Divers. 2010; 14:27-38.
21.Sahu NK, Kohli DV. Structural insight for imidazopyridazines as malarial kinase PfPK7 inhibitors using QSAR techniques. Med. Chem. 2012; 8:636-648.
22.Ajmani S, Kulkarni SA. A dual-response partial least squares regression QSAR model and its application in design of dual activators of PPAR and PPAR. QSAR Comb. Sci. 2008; 27:1291–1304.
23.Sahu NK, Shahi S, Sharma MC, Kohli DV. QSAR studies on imidazopyridazine derivatives as PfPK7 inhibitors. Mol. Simul. 2011; 37(9):752-765.