Novel GABA-AT inhibitors: QSAR and docking based virtual screening of phenyl substituted β-phenyl ethylidene hydrazine analogues

Sinha, Barij Nayan; Khosa, R. L.; Olson, Arthur J.

doi:10.1007/s00044-010-9390-6

Cited by 6 publications

(4 citation statements)

References 19 publications

(23 reference statements)

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“…The selected pharmacophore model corresponds to the CID 59533233 was depicted in Figure B. Test compounds were used to evaluate the models, Further docking and ADME studies used to validate the compound …”

Section: Resultsmentioning

confidence: 99%

Pharmacophore feature prediction and molecular docking approach to identify novel anti‐HCV protease inhibitors

Venkatesan

Rambabu

Jayanthi

et al. 2017

J of Cellular Biochemistry

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Discovering a potential drug for HCV treatment is a challenging task in the field of drug research. This study initiates with computational screening and modeling of promising ligand molecules. The foremost modeling method involves the identification of novel compound and its molecular interaction based on pharmacophore features. A total of 197 HCV compounds for NS3/4A protein target were screened for our study. The pharmacophore models were generated using PHASE module implemented in Schrodinger suite. The pharmacophore features include one hydrogen bond acceptor, one hydrogen bond donor, and three hydrophobic sites. As a result, based on mentioned hypothesis the model ADHHH.159 corresponds to the CID 59533233. Furthermore, docking was performed using maestro for all the 197 compounds. Among these, the CID 59533313 and 59533233 possess the best binding energy of −11.75 and − 10.40 kcal/mol, respectively. The interactions studies indicated that the CID complexed with the NS3/4A protein possess better binding affinity with the other compounds. Further the compounds were subjected to calculate the ADME properties. Therefore, it can be concluded that these two compounds could be a potential alternative drug for the development of HCV.

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Section: Resultsmentioning

confidence: 99%

Pharmacophore feature prediction and molecular docking approach to identify novel anti‐HCV protease inhibitors

Venkatesan

Rambabu

Jayanthi

et al. 2017

J of Cellular Biochemistry

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“…Docking calculations were carried out on 1OHV protein model. 10 Essential hydrogen atoms, Kollman united atom type charges, and solvation parameters were added with the aid of AutoDock tools. 18 The affinity (grid) maps of 20 A° grid points and 0.375 A° spacing were generated using the AutoGrid program (AutoGrid Systems, Redwood Shores, CA, USA).…”

Section: Molecular Dockingmentioning

confidence: 99%

“…9 Gamma amino butyric acid (GABA) has been proposed as a validated target for antiepileptic drugs, because its selective inhibition raises GABA concentration in the brain. 10 It is a pyridoxal phosphate (PLP)-dependent homodimeric enzyme, catalyzing reversible transfer of the amino group of GABA to α-ketoglutarate to yield succinic semialdehyde and L-glutamate. GABA-amino transferase (AT) is a homodimer with each subunit containing an active site PLP, covalently bound to LYS329 of chain A via a Schiff base.…”

Section: Introductionmentioning

confidence: 99%

Synthesis molecular modeling and anticonvulsant activity of some hydrazone, semicarbazone, and thiosemicarbazone derivatives of benzylidene camphor

Agrawal¹,

Jain²,

Kumar³

et al. 2014

RRMC

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Four series of 20 novel derivatives of benzylidene camphor with hydrazones, semicarbazones, and thiosemicarbazones were designed and synthesized. The newly synthesized compounds were evaluated for their anticonvulsant activity by maximal electroshock seizure model. Compounds showed varying degrees of anticonvulsant activity, most marked effect was observed for compounds 2f and 4d with lesser neurotoxicity. Molecular docking studies of most active compounds (2f and 4d) of the series revealed that they interact with LYS329A, GLN 301A, and THR 353B residues of 1OHV protein via hydrogen bonding and Pi interaction.

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“…In the design of other type of GABA-AT inhibitors via computational methods, Bansal has designed novel GABA-AT inhibitors based on a molecular field analysis k NN-MFA 3DQSAR model for phenyl-substituted β-phenylethylidene hydrazine analogues [38,39]. Davood, identified β-phenylethylidene hydrazide GABA analogues with a variety of substituents at the phenyl ring by QSAR techniques [40].…”

Section: Introductionmentioning

confidence: 99%

QSAR and Molecular Docking Studies of the Inhibitory Activity of Novel Heterocyclic GABA Analogues over GABA-AT

et al. 2018

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We have previously reported the synthesis, in vitro and in silico activities of new GABA analogues as inhibitors of the GABA-AT enzyme from Pseudomonas fluorescens, where the nitrogen atom at the γ-position is embedded in heterocyclic scaffolds. With the goal of finding more potent inhibitors, we now report the synthesis of a new set of GABA analogues with a broader variation of heterocyclic scaffolds at the γ-position such as thiazolidines, methyl-substituted piperidines, morpholine and thiomorpholine and determined their inhibitory potential over the GABA-AT enzyme from Pseudomonas fluorescens. These structural modifications led to compound 9b which showed a 73% inhibition against this enzyme. In vivo studies with PTZ-induced seizures on male CD1 mice show that compound 9b has a neuroprotective effect at a 0.50 mmole/kg dose. A QSAR study was carried out to find the molecular descriptors associated with the structural changes in the GABA scaffold to explain their inhibitory activity against GABA-AT. Employing 3D molecular descriptors allowed us to propose the GABA analogues enantiomeric active form. To evaluate the interaction with Pseudomonas fluorescens and human GABA-AT by molecular docking, the constructions of homology models was carried out. From these calculations, 9b showed a strong interaction with both GABA-AT enzymes in agreement with experimental results and the QSAR model, which indicates that bulky ligands tend to be the better inhibitors especially those with a sulfur atom on their structure.

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Novel GABA-AT inhibitors: QSAR and docking based virtual screening of phenyl substituted β-phenyl ethylidene hydrazine analogues

Cited by 6 publications

References 19 publications

Pharmacophore feature prediction and molecular docking approach to identify novel anti‐HCV protease inhibitors

Pharmacophore feature prediction and molecular docking approach to identify novel anti‐HCV protease inhibitors

Synthesis molecular modeling and anticonvulsant activity of some hydrazone, semicarbazone, and thiosemicarbazone derivatives of benzylidene camphor

QSAR and Molecular Docking Studies of the Inhibitory Activity of Novel Heterocyclic GABA Analogues over GABA-AT

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