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Combined 2D and 3D-QSAR, molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors.
SAR QSAR Environ Res. 2014; 25(11):905-37.SQ

Abstract

Selective inhibition of phosphodiesterase 2 (PDE2) in cells where it is located elevates cyclic guanosine monophosphate (cGMP) and acts as novel analgesic with antinociceptive activity. Three-dimensional quantitative structure-activity relationship (QSAR) studies for pyrazolodiazepinone inhibitors exhibiting PDE2 inhibition were performed using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and Topomer CoMFA, and two-dimensional QSAR study was performed using a Hologram QSAR (HQSAR) method. QSAR models were generated using training set of 23 compounds and were validated using test set of nine compounds. The optimum partial least squares (PLS) for CoMFA-Focusing, CoMSIA-SDH, Topomer CoMFA and HQSAR models exhibited good 'leave-one-out' cross validated correlation coefficient (q(2)) of 0.790, 0.769, 0.840 and 0.787, coefficient of determination (r(2)) of 0.999, 0.964, 0.979 and 0.980, and high predictive power (r(2)(pred)) of 0.796, 0.833, 0.820 and 0.803 respectively. Docking studies revealed that those inhibitors able to bind to amino acid Gln859 by cGMP binding orientation called 'glutamine-switch', and also bind to the hydrophobic clamp of PDE2 isoform, could possess high selectivity for PDE2. From the results of all the studies, structure-activity relationships and structural requirements for binding to active site of PDE2 were established which provide useful guidance for the design and future synthesis of potent PDE2 inhibitors.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Bhansali SG
a Department of Pharmaceutical Chemistry, Poona College of Pharmacy , Bharati Vidyapeeth Deemed University , Pune , Maharashtra , India.
Kulkarni VM
No affiliation info available

MeSH

Catalytic DomainComputer SimulationHydrophobic and Hydrophilic InteractionsLeast-Squares AnalysisModels, MolecularPhosphodiesterase InhibitorsPhosphoric Diester HydrolasesPyrazolesQuantitative Structure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25401514

Citation

Bhansali, S G., and V M. Kulkarni. "Combined 2D and 3D-QSAR, Molecular Modelling and Docking Studies of Pyrazolodiazepinones as Novel Phosphodiesterase 2 Inhibitors." SAR and QSAR in Environmental Research, vol. 25, no. 11, 2014, pp. 905-37.
Bhansali SG, Kulkarni VM. Combined 2D and 3D-QSAR, molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors. SAR QSAR Environ Res. 2014;25(11):905-37.
Bhansali, S. G., & Kulkarni, V. M. (2014). Combined 2D and 3D-QSAR, molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors. SAR and QSAR in Environmental Research, 25(11), 905-37. https://doi.org/10.1080/1062936X.2014.969309
Bhansali SG, Kulkarni VM. Combined 2D and 3D-QSAR, Molecular Modelling and Docking Studies of Pyrazolodiazepinones as Novel Phosphodiesterase 2 Inhibitors. SAR QSAR Environ Res. 2014;25(11):905-37. PubMed PMID: 25401514.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combined 2D and 3D-QSAR, molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors. AU - Bhansali,S G, AU - Kulkarni,V M, PY - 2014/11/18/entrez PY - 2014/11/18/pubmed PY - 2015/7/28/medline KW - 3D-QSAR KW - HQSAR KW - PDE2 KW - docking KW - pyrazolodiazepinone SP - 905 EP - 37 JF - SAR and QSAR in environmental research JO - SAR QSAR Environ Res VL - 25 IS - 11 N2 - Selective inhibition of phosphodiesterase 2 (PDE2) in cells where it is located elevates cyclic guanosine monophosphate (cGMP) and acts as novel analgesic with antinociceptive activity. Three-dimensional quantitative structure-activity relationship (QSAR) studies for pyrazolodiazepinone inhibitors exhibiting PDE2 inhibition were performed using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and Topomer CoMFA, and two-dimensional QSAR study was performed using a Hologram QSAR (HQSAR) method. QSAR models were generated using training set of 23 compounds and were validated using test set of nine compounds. The optimum partial least squares (PLS) for CoMFA-Focusing, CoMSIA-SDH, Topomer CoMFA and HQSAR models exhibited good 'leave-one-out' cross validated correlation coefficient (q(2)) of 0.790, 0.769, 0.840 and 0.787, coefficient of determination (r(2)) of 0.999, 0.964, 0.979 and 0.980, and high predictive power (r(2)(pred)) of 0.796, 0.833, 0.820 and 0.803 respectively. Docking studies revealed that those inhibitors able to bind to amino acid Gln859 by cGMP binding orientation called 'glutamine-switch', and also bind to the hydrophobic clamp of PDE2 isoform, could possess high selectivity for PDE2. From the results of all the studies, structure-activity relationships and structural requirements for binding to active site of PDE2 were established which provide useful guidance for the design and future synthesis of potent PDE2 inhibitors. SN - 1029-046X UR - https://www.unboundmedicine.com/medline/citation/25401514/Combined_2D_and_3D_QSAR_molecular_modelling_and_docking_studies_of_pyrazolodiazepinones_as_novel_phosphodiesterase_2_inhibitors_ DB - PRIME DP - Unbound Medicine ER -