Predicting the potency of hERG K+ channel inhibition by combining 3D-QSAR pharmacophore and 2D-QSAR models

2011 ◽  
Vol 18 (3) ◽  
pp. 1023-1036 ◽  
Author(s):  
Yayu Tan ◽  
Yadong Chen ◽  
Qidong You ◽  
Haopeng Sun ◽  
Manhua Li
Keyword(s):  
3D Qsar ◽  
K Channel ◽  
2D Qsar ◽  
Channel Inhibition ◽  
Qsar Models

Atom based 3D QSAR and Fingerprint based 2D QSAR of Novel Molecules as MmpL3 receptor inhibitors for Mycobacterium tuberculosis

2021 ◽  
pp. 6321-6329
Author(s):  
Poojita K ◽  
Fajeelath Fathima ◽  
Rajdeep Ray ◽  
Lalit Kumar ◽  
Ruchi Verma
Keyword(s):  
Health Care ◽  
Mycobacterium Tuberculosis ◽  
3D Qsar ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Urea Derivatives ◽  
2D Qsar ◽  
Qsar Models ◽  
Inhibition Property ◽  
Anti Tubercular Therapy

Tuberculosis is one of the leading cause of increase in mortality rate in today’s health care scenario. Due to increase frequency of drug resistant TB it is prudent to find new targets and promising targets for anti-tubercular activity. MmpL3 (Mycobacterial Membrane Protein Large 3) is one of the most effective and promiscuous targets for development of new drug for anti-tubercular therapy due to its cross resistance inhibition property. In this study we have presented atom based 3D QSAR and finger print based 2D QSAR models to study different structural and functional groups of Adamantyl urea derivatives and their action in MmpL3 inhibitory activity which will provide us the insight for designing better and far more effective anti TB drugs.

Identifying the Structural Features of Diphenyl Ether Analogues for InhA Inhibition: A 2D and 3D QSAR Based Study

2019 ◽  
Vol 17 (1) ◽  
pp. 31-47 ◽  
Author(s):  
Ashutosh Prasad Tiwari ◽  
Varadaraj Bhat Giliyar ◽  
Gurypur Gautham Shenoy ◽  
Vandana Kalwaja Eshwara
Keyword(s):  
Inhibitory Activity ◽  
Diphenyl Ether ◽  
3D Qsar ◽  
Qsar Model ◽  
Structural Features ◽  
Mycolic Acids ◽  
2D Qsar ◽  
Qsar Models ◽  
Mycobacterial Cell Wall ◽  
2D And 3D

Background: Enoyl acyl carrier protein reductase (InhA) is a validated target for Mycobacterium. It is an enzyme which is associated with the biosynthesis of mycolic acids in type II fatty acid synthase system. Mycobacterial cell wall majorly comprises mycolic acids, which are responsible for virulence of the microorganism. Several diphenyl ether derivatives have been known to be direct inhibitors of InhA. Objective: In the present work, a Quantitative Structure Activity Relationship (QSAR) study was performed to identify the structural features of diphenyl ether analogues which contribute to InhA inhibitory activity in a favourable way. Method: Both 2D and 3D QSAR models were built and compared. Several fingerprint based 2D QSAR models were generated and their relationship with the structural features was studied. Models which corroborated the inhibitory activity of the molecules with their structural features were selected and studied in detail. Results: A 2D-QSAR model, with dendritic fingerprints having regression coefficient, for test set molecules Q2 =0.8132 and for the training set molecules, R2 =0.9607 was obtained. Additionally, an atom-based 3D-QSAR model with Q2 =0.7697 and R2 =0.9159 was also constructed. Conclusion: The data reported by various models provides guidance for the designing of structurally new diphenyl ether inhibitors with potential activity against InhA of M. tuberculosis.

Insilico studies, synthesis and antitubercular activity of some novel quinoline – azitidinone derivatives

2020 ◽  
Vol 16 ◽  
Author(s):  
Trupti. S. Chitre ◽  
Kalyani. D. Asgaonkar ◽  
Amrut B. Vikhe ◽  
Shital M Patil ◽  
Dinesh. R. Garud ◽  
...  
Keyword(s):  
Combinatorial Library ◽  
3D Qsar ◽  
Antitubercular Activity ◽  
Structural Features ◽  
Docking Studies ◽  
Quinoline Derivatives ◽  
Qsar Models ◽  
Molecular Modeling Studies ◽  
Lead Generation ◽  
Mcf 7

Background: Diarylquinolines like Bedaquiline have shown promising antitubercular activity by their action of Mycobacterial ATPase. Objective: The structural features necessary for good antitubercular activity for a series of quinoline derivatives were explored through computational chemistry tools like QSAR and combinatorial library generation. In the current study, 3-Chloro-4-(2-mercaptoquinoline-3-yl)-1-substitutedphenylazitidin-2-one derivatives have been designed and synthesized based on molecular modeling studies as anti-tubercular agents. Method: 2D and 3DQSAR analysis was used to designed compounds having quinoline scaffold. The synthesized compounds were evaluated against active and dormant strains of Mycobacterium tuberculosis (MTB) H37 Ra and Mycobacterium bovis BCG. The compounds were also tested for cytotoxicity against MCF-7, A549 and Panc-1 cell lines using MTT assay. Binding affinity of designed compounds was gauged by molecular docking studies. Results: Statistically significant QSAR models generated by SA-MLR method for 2D QSAR exhibited r2 = 0.852, q2 = 0.811and whereas 3D QSAR with SA-kNN showed q2 = 0.77. The synthesized compounds exhibited MIC in the range of 1.38-14.59(µg/ml) .These compounds showed some crucial interaction with MTB Atpase. Conclusion: The present study has shown some promising results which can be further explored for lead generation.

Involvement of actin cytoskeleton in modulation of apical K channel activity in rat collecting duct

1994 ◽  
Vol 267 (4) ◽  
pp. F592-F598 ◽  
Author(s):  
W. H. Wang ◽  
A. Cassola ◽  
G. Giebisch
Keyword(s):  
Actin Cytoskeleton ◽  
Actin Filaments ◽  
Cytochalasin B ◽  
Collecting Duct ◽  
K Channel ◽  
Cortical Collecting Duct ◽  
Channel Activity ◽  
Patch Clamp Technique ◽  
Channel Inhibition ◽  
Inside Out

We have employed the patch-clamp technique to investigate the role of the actin cytoskeleton in the modulation of the low-conductance K+ channel in the apical membrane of the rat cortical collecting duct (CCD). This K+ channel is inactivated by application of cytochalasin B or D, both compounds known to disrupt actin filaments. The effect of both cytochalasins, B and D, was fully reversible in cell-attached patches, but channel activity could not be fully restored in excised membrane patches. The effect of cytochalasins on channel activity was specific and resulted from depolymerization of the actin cytoskeleton, since application of 10 microM chaetoglobosin C, a cytochalasin analogue that does not depolymerize the actin filaments, had no effect on channel activity in inside-out patches. Addition of either actin monomers or of the polymerizing actin filaments in inside-out patches to the cytosolic medium had no effect on channel activity. This suggests that cytochalasin B- or D-induced inactivation of apical K+ channels is not caused by obstruction of the channel pore by actin. We also observed that channel inhibition by cytochalasin B or D could be blocked by pretreatment with 5 microM phalloidin, a compound that stabilizes actin filaments. We conclude that apical K+ channel activity depends critically on the integrity of the actin cytoskeleton.

scholarly journals Design, Synthesis, Biological Evaluation, and Molecular Modeling of 2-Difluoromethylbenzimidazole Derivatives as Potential PI3Kα Inhibitors

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 387
Author(s):  
Xiangcong Wang ◽  
Moxuan Zhang ◽  
Ranran Zhu ◽  
Zhongshan Wu ◽  
Fanhong Wu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Modeling ◽  
3D Qsar ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Field Analysis ◽  
Dynamics Simulation ◽  
Comfa Model ◽  
Qsar Models

PI3Kα is one of the potential targets for novel anticancer drugs. In this study, a series of 2-difluoromethylbenzimidazole derivatives were studied based on the combination of molecular modeling techniques 3D-QSAR, molecular docking, and molecular dynamics. The results showed that the best comparative molecular field analysis (CoMFA) model had q2 = 0.797 and r2 = 0.996 and the best comparative molecular similarity indices analysis (CoMSIA) model had q2 = 0.567 and r2 = 0.960. It was indicated that these 3D-QSAR models have good verification and excellent prediction capabilities. The binding mode of the compound 29 and 4YKN was explored using molecular docking and a molecular dynamics simulation. Ultimately, five new PI3Kα inhibitors were designed and screened by these models. Then, two of them (86, 87) were selected to be synthesized and biologically evaluated, with a satisfying result (22.8 nM for 86 and 33.6 nM for 87).

Construction of 3D-QSAR Models Using the 4D-QSAR Analysis Formalism

1997 ◽  
Vol 119 (43) ◽  
pp. 10509-10524 ◽  
Author(s):  
A. J. Hopfinger ◽  
Shen Wang ◽  
John S. Tokarski ◽  
Baiqiang Jin ◽  
Magaly Albuquerque ◽  
...  
Keyword(s):  
3D Qsar ◽  
Qsar Analysis ◽  
Qsar Models

scholarly journals Metabolic inhibition impairs ATP-sensitive K+ channel block by sulfonylurea in pancreatic β-cells

1998 ◽  
Vol 274 (1) ◽  
pp. E38-E44 ◽  
Author(s):  
Eri Mukai ◽  
Hitoshi Ishida ◽  
Seika Kato ◽  
Yoshiyuki Tsuura ◽  
Shimpei Fujimoto ◽  
...  
Keyword(s):  
Metabolic Inhibition ◽  
K Channel ◽  
High Dose ◽  
Dependent Manner ◽  
Channel Activity ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Patch Clamp Technique ◽  
Channel Inhibition ◽  
Dose Dependent

The effect of metabolic inhibition on the blocking of β-cell ATP-sensitive K+ channels (KATP channels) by glibenclamide was investigated using a patch-clamp technique. Inhibition of KATP channels by glibenclamide was attenuated in the cell-attached mode under metabolic inhibition induced by 2,4-dinitrophenol. Under a low concentration (0.1 μM) of ATP applied in the inside-out mode, KATP channel activity was not fully abolished, even when a high dose of glibenclamide was applied, in contrast to the dose-dependent and complete KATP channel inhibition under 10 μM ATP. On the other hand, cibenzoline, a class Ia antiarrhythmic agent, inhibits KATP channel activity in a dose-dependent manner and completely blocks it, even under metabolic inhibition. In sulfonylurea receptor (SUR1)- and inward rectifier K+ channel (Kir6.2)-expressed proteins, cibenzoline binds directly to Kir6.2, unlike glibenclamide. Thus, KATPchannel inhibition by glibenclamide is impaired under the condition of decreased intracellular ATP in pancreatic β-cells, probably because of a defect in signal transmission between SUR1 and Kir6.2 downstream of the site of sulfonylurea binding to SUR1.

Effects of cytochrome P-450 inhibitors on ionic currents in isolated rat type I carotid body cells

1996 ◽  
Vol 271 (1) ◽  
pp. C85-C92 ◽  
Author(s):  
C. J. Hatton ◽  
C. Peers
Keyword(s):  
Carotid Body ◽  
Single Channel ◽  
Ionic Currents ◽  
K Channel ◽  
Type I ◽  
Type I Cells ◽  
Channel Inhibition ◽  
Cytochrome P 450 ◽  
I Cells ◽  
K Currents

Hypoxic chemoreception in the carotid body involves selective inhibition of K+ channels in type I cells. We have investigated whether cytochrome P-450 may act as an O2 sensor coupling hypoxia to K+ channel inhibition, by investigating the actions of P-450 inhibitors to modulate channel activity (recorded using patch-clamp techniques) in type I cells isolated from 8-to 12-day-old rat pups. The imidazole antimycotic P-450 inhibitors miconazole and clotrimazole (1-10 microM) inhibited the Ca(2+)-activated (KCa) and voltage-gated K+ (Kv) currents in isolated type I cells. Single-channel recordings indicated that the KCa channels could be inhibited directly by miconazole. Miconazole also irreversibly inhibited Ca2+ channel currents. By contrast, acute application of the suicide substrate P-450 inhibitor, 1-aminobenzotriazole (1-ABT; 3 mM) was without effect on K+ or Ca2+ currents. Hypoxia (16-23 mmHg) reversibly inhibited K+ currents and prevented the inhibitory actions of miconazole. Furthermore, the inhibitory actions of miconazole could be partially reversed by hypoxia. Pretreatment of cells for 60 min with 3 mM 1-ABT substantially reduced the inhibitory actions of hypoxia on K+ currents. Our results indicate that imidazole antimycotic P-450 inhibitors can directly and nonselectively inhibit ionic channels in type I cells but, more importantly, provide evidence to suggest that hypoxic inhibition of K+ currents in type I cells is mediated in part at least by cytochrome P-450.

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