Kinetic and in silico analysis of thiazolidin-based inhibitors of α-carbonic anhydrase isoenzymes.

Durdagi, Serdar/0000-0002-0426-0905 WOS: 000314531000019 PubMed: 23173744 Carbonic anhydrases (CAs, EC 4.2.1.1) are inhibited by sulfonamides, inorganic anions, phenols, salicylic acid derivatives (acting as drug or prodrugs). A novel class of CA inhibitors (CAIs), interacting with the CA isozymes I and II (cytosolic) in a different manner, is reported here. Kinetic measurements allowed us to identify thiazolidin-based compounds as submicromolar-low micromolar inhibitors of these two CA isozymes. Molecular docking studies of a set of such inhibitors within CA I and II active site allowed us to understand the inhibition mechanism. This new class of inhibitors bind differently compared to other classes of inhibitors known to date: they were found between the phenol-binding site, filling thus the middle of the enzyme cavity

An effort to discover the preferred conformation of the potent AMG3 cannabinoid analog when reaching the active sites of the cannabinoid receptors

Most of current 3D-QSAR algorithms use alignments of compounds at the training set based on reference active ligands in the first step of the construction of the pharamacophore modeling. This first step mostly defines the success of constructed pharmacophore models. In this step, it is essential to find the bioactive conformation for solid and reliable 3D-QSAR models. Therefore, we have proceeded through different approaches for revealing the preferred conformations of Δ(8)-THC derivative AMG-3 at CB1 and CB2 receptors. In the first approach, we have applied conformational search methods in gas and in solvent phases for the ligand. The derived low energy conformers using these methodologies have been modeled through 3D-QSAR studies (first generation model). In the second approach, the low energy conformers derived from molecular docking studies have been used as input for 3D-QSAR studies (second generation model). In the current study, a new approach using MD calculations in a simulated biological environment, thus the CB receptors surrounded by a lipid bilayer environment has been used (third generation). The obtained results for different environments were compared and the approach deriving the highest statistic results was used for the generation of the novel AMG3 analogs for optimal and selective binding affinities at CB1 and CB2 receptors by the de novo drug design modeling

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

CDK2/cyclin A has appeared as an attractive drug targets over the years with diverse therapeutic potentials. A computational strategy based on comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) followed by molecular docking studies were performed on a series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent CDK2/cyclin A inhibitors. The CoMFA and CoMSIA models, using 38 molecules in the training set, gave r2cv values of 0.747 and 0.518 and r2 values of 0.970 and 0.934, respectively. 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. Molecular docking was applied to explore the binding mode between the ligands and the receptor. The information obtained from molecular modeling studies may be helpful to design novel inhibitors of CDK2/cyclin A with desired activity

In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome

Accurate diagnosis of predisposition to long QT syndrome is crucial for reducing the risk of cardiac arrhythmias. In recent years, drug-induced provocative tests have proved useful to unmask some latent mutations linked to cardiac arrhythmias. In this study we expanded this concept by developing a prototype for a computational provocative screening test to reveal genetic predisposition to acquired long-QT syndrome (aLQTS). We developed a computational approach to reveal the pharmacological properties of I blocking drugs that are most likely to cause aLQTS in the setting of subtle alterations in I channel gating that would be expected to result from benign genetic variants. We used the model to predict the most potentially lethal combinations of kinetic anomalies and drug properties. In doing so, we also implicitly predicted ideal inverse therapeutic properties of K channel openers that would be expected to remedy a specific defect We systematically performed "in silico mutagenesis" by altering discrete kinetic transition rates of the Fink et al. Markov model of human l channels, corresponding to activation, inactivation, deactivation and recovery from inactivation of I-Kr channels. We then screened and identified the properties of IKr blockers that caused acquired long QT and therefore unmasked mutant phenotypes for mild, moderate and severe variants. Mutant I-Kr channels were incorporated into the O'Hara et al. human ventricular action potential (AP) model and subjected to simulated application of a wide variety of I-drug interactions in order to identify the characteristics that selectively exacerbate the AP duration (APD) differences between wild-type and IKr mutated cells. Our results show that drugs with disparate affinities to conformation states of the I-Kr, channel are key to amplify variants underlying susceptibility to acquired long QT syndrome, an effect that is especially pronounced at slow frequencies. Finally, we developed a mathematical formulation of the M54T MiRP1 latent mutation and simulated a provocative test. In this setting, application of dofetilide dramatically amplified the predicted QT interval duration in the M54T hMiRP1 mutation compared to wild-type.This work was partially supported by the "VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica" from the Ministerio de Economia y Competitividad of Spain (TIN2012-37546-CO3-01) and the European Commission (European Regional Development Funds - ERDF-FEDER), Programa de Apoyo a la Investigacion y Desarrollo de la Universidad Politecnica de Valencia (PAID-00-10-3212) to L.R., Direccion General de Politica Cientifica de la Generalitat Valenciana (GV/2013/119), and Programa Prometeo de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana (PROMETEO/ 2012/030). The research was also supported by the American Heart Association (GIAs (10GRNT3880050, 13GRNT14370019), Western States Affiliate), Alfred P. Sloan Foundation, the National Institutes of Health NHLBI R01-HL-085592 and a research grant from Gilead Sciences (to CEC).Romero Pérez, L.; Trénor Gomis, BA.; Yang, P.; Saiz Rodríguez, FJ.; Clancy, CE. (2014). In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome. Journal of Molecular and Cellular Cardiology. 72:126-137. https://doi.org/10.1016/j.yjmcc.2014.02.018S1261377

Application of 3D QSAR CoMFA/CoMSIA and in silico docking studies on novel renin inhibitors against cardiovascular diseases

For the first time, a set of renin inhibitors were subjected to the 3D QSAR/CoMFA and CoMSIA studies. The utility of renin inhibitors in the treatment of cardiovascular diseases has not been fully explored yet. At the moment, aliskiren is the first and only existing renin inhibitor in the drug market. The performed 3D QSAR/CoMFA and CoMSIA in combination with docking studies included aliskiren and 37 derivatives possessing a wide variety of bioactivity. The obtained results may aid in the design of novel bioactive renin inhibitors

Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify the thermal properties of lipid bilayers more significantly than methylated congeners. These distinct differential properties were attributed to the fact that phenolic hydroxyl groups constitute an anchoring group in the vicinity of the headgroup, while the methylated analogs are embedded deeper towards the hydrophobic region of the lipid bilayers. In this work the thermal effects of synthetic polyphenolic stilbenoid analogs and their methylated congeners have been studied using differential scanning calorimetry (DSC).Molecular dynamics (MD) simulations have been performed to explain the DSC results. Thus, two of their phenolic hydroxyl groups orient in the lipid bilayers in such a way that they anchor in the region of the headgroup. In contrast, their methoxy congeners cannot anchor effectively and are embedded deeper in the hydrophobic segment of the lipid bilayers. The MD results explain the fact that hydroxystilbenoid analogs exert more significant effects on the pretransition than their methoxy congeners, especially at low concentrations. To maximize the polar interactions, the two phenolic hydroxyl groups are localized in the vicinity of the head-group region, directing the remaining hydroxy group in the hydrophobic region. This topographical position of stilbenoid analogs forms a mismatch that explains the significant broadening of the width of the phase transition and lowering of the main phasetransition temperature in the lipid bilayers. At high concentrations, hydroxy and nonhydroxy analogs appear to form different domains. The correlation of thermal effects with antioxidant activity is discusse

Investigation of the Structure Requirement for 5-HT6 Binding Affinity of Arylsulfonyl Derivatives: A Computational Study

5-HT6 receptor has been implicated in a series of diseases including anxiety, depression, schizophrenia and cognitive dysfunctions. 5-HT6 ligands have been reported to play a significant role in the treatment for central nervous system (CNS) diseases. Presently, a large series of 223 5-HT6 ligands were studied using a combinational method by 3D-QSAR, molecular docking and molecular dynamics calculations for further improvement of potency. The optimal 3D models exhibit satisfying statistical results with r2ncv, q2 values of 0.85 and 0.50 for CoMFA, 0.81 and 0.53 for CoMSIA, respectively. Their predictive powers were validated by external test set, showing r2pred of 0.71 and 0.76. The contour maps also provide a visual representation of contributions of steric, electrostatic, hydrophobic and hydrogen bond fields as well as the prospective binding models. In addition, the agreement between 3D-QSAR, molecular docking and molecular dynamics simulation proves the rationality of the developed models. These results, we hope, may be helpful in designing novel and potential 5-HT6 ligands

A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current

[EN] Background: The QT interval is a phase of the cardiac cycle that corresponds to action potential duration (APD) including cellular repolarization (T-wave). In both clinical and experimental settings, prolongation of the QT interval of the electrocardiogram (ECG) and related proarrhythmia have been so strongly associated that a prolonged QT interval is largely accepted as surrogate marker for proarrhythmia. Accordingly, drugs that prolong the QT interval are not considered for further preclinical development resulting in removal of many promising drugs from development. While reduction of drug interactions with hERG is an important goal, there are promising means to mitigate hERG block. Here, we examine one possibility and test the hypothesis that selective inhibition of the cardiac late Na current (I-NaL) by the novel compound GS-458967 can suppress proarrhythmic markers. Methods and results: New experimental data has been used to calibrate INaL in the Soltis-Saucerman computationally based model of the rabbit ventricular action potential to study effects of GS-458967 on INaL during the rabbit ventricular AP. We have also carried out systematic in silico tests to determine if targeted block of INaL would suppress proarrhythmia markers in ventricular myocytes described by TRIaD: Triangulation, Reverse use dependence, beat-to-beat Instability of action potential duration, and temporal and spatial action potential duration Dispersion. Conclusions: Our computer modeling approach based on experimental data, yields results that suggest that selective inhibition of INaL modifies all TRIaD related parameters arising from acquired Long-QT Syndrome, and thereby reduced arrhythmia risk. This study reveals the potential for adjunctive pharmacotherapy via targeted block of INaL to mitigate proarrhythmia risk for drugs with significant but unintended off-target hERG blocking effects.The National Institutes of Health R01 HL128537-01 (CEC), U01 HL126273-01 (CEC) and R01HL128170-02 (CEC).Yang, P.; El-Bizri, N.; Romero Pérez, L.; Giles, W.; Rajamani, S.; Belardinelli, L.; Clancy, CE. (2016). A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current. Journal of Molecular and Cellular Cardiology. 99:151-161. https://doi.org/10.1016/j.yjmcc.2016.08.011S1511619