Molecular Modeling Studies of 4,5-Dihydro-1H-pyrazolo[4,3-h] quinazoline Derivatives as Potent CDK2/Cyclin A Inhibitors Using 3D-QSAR and Docking

Ai, Yong; Wang, Shao-Teng; Sun, Ping‐Hua; Song, Fa-Jun

doi:10.3390/ijms11103705

Cited by 21 publications

(11 citation statements)

References 27 publications

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“…In the CoMFA model, the contributions of the steric and electrostatic fields to activity were 40.9% and 59.1%. The yellow and blue contours located at the A site indicated that a bulky substituent would not be tolerated and electropositive groups would be favorable [22]. However, bulky substituents and electropositive groups would not be favorable to the B group (Figure 4a) [23].…”

Section: Resultsmentioning

confidence: 99%

Combined Pharmacophore Modeling, 3D-QSAR, Homology Modeling and Docking Studies on CYP11B1 Inhibitors

Wang

et al. 2015

Molecules

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Abstract:The mitochondrial cytochrome P450 enzymes inhibitor steroid 11β-hydroxylase (CYP11B1) can decrease the production of cortisol. Therefore, these inhibitors have an effect in the treatment of Cushing's syndrome. A pharmacophore model generated by Genetic Algorithm with Linear Assignment for Hypermolecular Alignment of Datasets (GALAHAD) was used to align the compounds and perform comparative molecular field analysis (CoMFA) with Q 2 = 0.658, R 2 = 0.959. The pharmacophore model contained six hydrophobic regions and one acceptor atom, and electropositive and bulky substituents would be tolerated at the A and B sites, respectively. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study based on the alignment with the atom root mean square (RMS) was applied using comparative molecular field analysis (CoMFA) with Q 2 = 0.666, R 2 = 0.978, and comparative molecular similarity indices analysis (CoMSIA) with Q 2 = 0.721, R 2 = 0.972. These results proved that all the models have good predictability of the bioactivities of inhibitors. Furthermore, the QSAR models indicated that a hydrogen bond acceptor substituent would be disfavored at the A and B groups, OPEN ACCESSMolecules 2015, 20 1015 while hydrophobic groups would be favored at the B site. The three-dimensional (3D) model of the CYP11B1 was generated based on the crystal structure of the CYP11B2 (PDB code 4DVQ). In order to probe the ligand-binding modes, Surflex-dock was employed to dock CYP11B1 inhibitory compounds into the active site of the receptor. The docking result showed that the imidazolidine ring of CYP11B1 inhibitors form H bonds with the amino group of residue Arg155 and Arg519, which suggested that an electronegative substituent at these positions could enhance the activities of compounds. All the models generated by GALAHAD QSAR and Docking methods provide guidance about how to design novel and potential drugs for Cushing's syndrome treatment.

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Section: Resultsmentioning

confidence: 99%

Combined Pharmacophore Modeling, 3D-QSAR, Homology Modeling and Docking Studies on CYP11B1 Inhibitors

Wang

et al. 2015

Molecules

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“…The Surflex-Dock uses an empirical scoring function and a patented search engine to dock ligands into a protein’s binding site [18]. The scoring function considers the four terms, including the hydrophobic complementarity, polar complementarity, entropic terms and solvation terms.…”

Section: Methodsmentioning

confidence: 99%

Combined 3D-QSAR and Docking Modelling Study on Indolocarbazole Series Compounds as Tie-2 Inhibitors

Tian

et al. 2011

IJMS

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Tie-2, a kind of endothelial cell tyrosine kinase receptor, is required for embryonic blood vessel development and tumor angiogenesis. Several compounds that showed potent activity toward this attractive anticancer drug target in the assay have been reported. In order to investigate the structure-activity correlation of indolocarbazole series compounds and modify them to improve their selectivity and activity, 3D-QSAR models were built using CoMFA and CoMSIA methods and molecular docking was used to check the results. Based on the common sketch align, two good QSAR models with high predictabilities (CoMFA model: q2 = 0.823, r2 = 0.979; CoMSIA model: q2 = 0.804, r2 = 0.967) were obtained and the contour maps obtained from both models were applied to identify the influence on the biological activity. Molecular docking was then used to confirm the results. Combined with the molecular docking results, the detail binding mode between the ligands and Tie-2 was elucidated, which enabled us to interpret the structure-activity relationship. These satisf actory results not only offered help to comprehend the action mechanism of indolocarbazole series compounds, but also provide new information for the design of new potent inhibitors.

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“…The 3D structures of all compounds were constructed by using the Sketch Molecule module. Energy minimization of each structure was performed using the SYBYL energy minimizer Tripos force field and Gasteiger-Hückel charge [ 13 , 14 ]. Molecular alignment was considered as one of the most sensitive parameters in 3D-QSAR analysis [ 15 , 16 ].…”

Section: Methodsmentioning

confidence: 99%

“…In this equation, SD is the sum of the squared deviations between the agonistic activities of the test set and the mean activity of the training molecules and PRESS is the sum of squared deviations between predicted and actual activity values for each molecule in the test set [ 13 , 24 , 25 , 26 ].…”

Section: Methodsmentioning

confidence: 99%

Molecular Modeling Studies on 11H-Dibenz[b,e]azepine and Dibenz[b,f][1,4]oxazepine Derivatives as Potent Agonists of the Human TRPA1 Receptor

Song

Wang

et al. 2010

Molecules

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A computational strategy based on comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was performed on a series of the 11H-dibenz[b,e]azepine and dibenz[b,f][1,4]oxazepine derivatives as potent agonists of the human TRPA1 receptor. The CoMFA and CoMSIA models resulting from a 21 molecule training set gave r2cv values of 0.631 and 0.542 and r2 values of 0.986 and 0.981, respectively. The statistically significant models were validated by a test set of five compounds with predictive r2pred. values of 0.967 and 0.981 for CoMFA and CoMSIA, respectively. A systemic external validation was also performed on the established models. The information obtained from 3D counter maps could facilitate the design of more potent human TRPA1 receptor agonists.

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Molecular Modeling Studies of 4,5-Dihydro-1H-pyrazolo[4,3-h] quinazoline Derivatives as Potent CDK2/Cyclin A Inhibitors Using 3D-QSAR and Docking

Cited by 21 publications

References 27 publications

Combined Pharmacophore Modeling, 3D-QSAR, Homology Modeling and Docking Studies on CYP11B1 Inhibitors

Combined Pharmacophore Modeling, 3D-QSAR, Homology Modeling and Docking Studies on CYP11B1 Inhibitors

Combined 3D-QSAR and Docking Modelling Study on Indolocarbazole Series Compounds as Tie-2 Inhibitors

Molecular Modeling Studies on 11H-Dibenz[b,e]azepine and Dibenz[b,f][1,4]oxazepine Derivatives as Potent Agonists of the Human TRPA1 Receptor

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