Quantitative Structure Activity Relationships Study of Soluble Epoxide Hydrolase Inhibitors Using MLR, ANN, CoMFA and CoMSIA Methods

Abstract

Soluble epoxide hydrolase (sEH), a member of the α/β hydrolase fold family, catalyzes the hydrolysis of epoxy eicosatrienoic acids to vicinal diol which are involved in the regulation of blood pressure and inflammation. In this study, 2D and 3D‐QSAR analysis of novel N,N′‐disubstituted urea derivatives as sEH inhibitors were performed by stepwise multiple linear regressions (SW‐MLR), stepwise artificial neural networks (SW‐ANN), Comparative Molecular Field Analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). It was found that SW‐MLR model with r2 of 0.954 for the training set and r2 of 0.876 for the test set were more favorable than model established by CoMFA method with r2=0.983, r2pred=0.602 and CoMSIA with r2=0.987, r2pred=0.751 in 3D‐QSAR. In addition, obtaining models were validated by cross validation with cut off value of q2> 0.5. These developed models could be a useful guideline to design and predict the activity of novel compounds with enhanced sEH inhibitory activities.

Computational and Retrosynthetic Investigation of Isoxazole‐Bearing Chalcones as Antioxidant Activate Compounds

“…The same procedure is followed to calculate the fields that characterize CoMSIA analysis [8] . Gaussian function was employed in the CoMSIA model to estimate the distance between atoms in molecules and atoms in the probe [8] …”

“…A threshold of 30 kcal mol −1 is set as the energy cut‐off value, and the other criteria are taken by default [7] . The same procedure is followed to calculate the fields that characterize CoMSIA analysis [8] . Gaussian function was employed in the CoMSIA model to estimate the distance between atoms in molecules and atoms in the probe [8] …”

“…[8] Gaussian function was employed in the CoMSIA model to estimate the distance between atoms in molecules and atoms in the probe. [8] Table 2 depicts the different CoMFA and CoMSIA models based on various fields. The CoMFA-SE and CoMSIA-SHA models produced excellent q 2 values (0.814 and 0.895, respectively) with an ONC (1, and 2, respectively), r 2 values (0.929, and 0.980, respectively), r 2 values (0.924, and 0.966, respectively), reliable SEE values (0.111, and 0.063, respectively) and a Fisher test (104.827, and 172.735, respectively).…”

“…Khlebnikov outlined them as anything that either directly or indirectly controls antioxidant defenses, inhibits the generation of ROS (Reactive Oxygen Species), or directly catches ROS. [2] Several izoxazole-based compounds are known for their antioxidant activities, among which compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) subject of this study, were synthesized by the Claisen-Schmidt condensation reaction in the presence of aqueous potassium as a catalyst (Scheme 1). [3] The antioxidant activity of these compounds was evaluated using the DPPH (1,1-diphenyl-2picrylhydrazine) free radical test, according to the method described by Brand-Williams et al Gallic acid was used as a positive control.…”

Synthesis, Docking Study and Biological Evaluation of Amide‐Based Soluble Epoxide Hydrolase Inhibitors with Novel Secondary Pharmacophore of Pyrimidin‐2‐ol

“…In these compounds, two pharmacophores of amide and pyrimidin-2-ol ring were linked by a phenylene ring, and a para-substituted phenyl ring was considered the second linker-third pharmacophore (L 2 P 3 ) (Figure 2). [11,[18][19][20][21] Additionally, molecular docking analysis was performed based on the results from our previous published article [22] to reveal the significant interactions between the key pharmacophores of the synthesized compounds and active residues in terms of binding affinities. In our previous study, an extensive in silico study was performed to investigate the binding affinities of the newly synthesized quinazoline-4(3H)-one and 4,6-disubstituted pyridin-2(1H)-one derivatives against sEH enzyme.…”