A potential risk factor for paraoxonase 1: in silico and in-vitro analysis of the biological activity of proton-pump inhibitors†

Abstract

Objectives Proton‐pump inhibitors (PPIs) are drugs commonly utilized by about 7% of adults in the world. Recent researches have shown that there are countless and severe side effects of these drugs. This situation has raised concern among clinicians and patients alike. The purpose of this study is to contribute the novel drug discovery and development technology and toxicology field by researching interactions of PPIs on paraoxonase 1. Methods In this study, the paraoxonase 1 enzyme was purified from human serum by using rapid and straightforward chromatographic techniques. Subsequently, the inhibition effects of pantoprazole, omeprazole, and esomeprazole, PPIs, were investigated on paraoxonase 1. Besides, molecular docking studies were performed to unravel the binding mechanism between the enzyme and drugs. Key findings All drugs showed potent inhibitory activities. IC50 of the drugs values were 54.780 ± 0.524, 86.470 ± 0.818 and 93.390 ± 0.885 mm and Ki constants were found as 39.895 ± 0.005 mm, 70.112 ± 0.010 mm and 78.868 ± 0.008 mm, respectively. The binding scores observed in silico studies were found to agree with the obtained from in‐vitro experimental results. Conclusions We observed that the drugs decreased PON1 activity at low concentrations. The results show that adjusting the dosages of these medications is a crucial case for each patient. The physicians should more carefully interpret whether there is an essential indication before prescribing PPIs and, if there is, to approve the proper dosing for the situation.

Synthesis, characterization, biological evaluation, and in silico studies of novel 1,3‐diaryltriazene‐substituted sulfathiazole derivatives

“…[73] The ligands were optimized in the OPLS3e force field [74] using the LigPrep module. [75] The boxes enclosing the centroid of cocrystallized ligands (CJK, 53X, AA7, and N0J, respectively) were set as the grid by Receptor Grid Generation [76] in Maestro. Ligands were docked with the extra precision mode (XP) [77] of Glide, and the poses showing the highest docking score values and suitable binding interactions were subjected to an MM-GBSA (molecular mechanics/generalized Born surface area)-based refinement [78] in the Prime module.…”

New Isoindole‐1,3‐dione Substituted Sulfonamides as Potent Inhibitors of Carbonic Anhydrase and Acetylcholinesterase: Design, Synthesis, and Biological Evaluation

“…The molecular docking analyses were performed to affirm the binding characteristics of isoindole‐1,3‐dione substituted sulfonamides ( 3, 4 a – k ) on hCA isoforms I, II and AChE receptors. Firstly, docking parameters and prepared grids were validated by re‐docking the native ligands 2,3,5,6‐tetrafluoro‐4‐(propylsulfanyl)benzenesulfonamide (C 9 H 9 F 4 NO 2 S 2; 3TV), 4‐[(4,6‐dimethylpyrimidin‐2‐yl)thio]‐2,3,5,6‐tetrafluorobenzenesulfonamide (C 12 H 9 F 4 N 3 O 2 S 2 ; V50), and 1‐benzyl‐4‐[(5,6‐dimethoxy‐1‐indanon‐2‐yl)methyl]piperidine (C 24 H 29 NO 3 ; E20) into respective grids of hCA I, II, and AChE, respectively.…”

“…The molecular docking analyses [46][47][48][49][50][51] were performed to affirm the binding characteristics of isoindole-1,3-dione substituted sulfonamides (3, 4 a-k) on hCA isoforms I, II and AChE receptors. Firstly, docking parameters and prepared grids were validated by re-docking the native ligands 2,3,5,6-tetrafluoro-4-(propylsulfanyl)benzenesulfonamide (C 9 H 9 F 4 NO 2 S 2; 3TV), [52] 4- Table 5.…”

In Vitro and In Silico Studies on the Toxic Effects of Antibacterial Drugs as Human Serum Paraoxonase 1 Inhibitor

“…We also indicated that moxifloxacin hydrochloride had competitive, whereas the others showed non‐competitive inhibition . Also, in our other studies, we selected the drugs, such as diverse nucleoside analogs (gemcitabine hydrochloride, acyclovir, and 5‐fluorouracil), some calcium channel blockers (nifedipine, nitrendipine, isradipine, and amlodipine besylate), various antineoplastic medicates (palonosetron hydrochloride, bevacizumab, and cyclophosphamide), several chemotherapeutic agents (vincristine sulfate, epirubicin hydrochloride, and doxorubicin hydrochloride), some gadolinium‐based contrast agents (gadoteric acid, gadopentetic acid, gadoxetate disodium, and gadodiamide), and certain proton‐pump inhibitors (pantoprazole, omeprazole, and esomeprazole) for investigation of inhibition effects against human serum PON1 activity. We determined that most of these drugs used in the tests, despite being at therapeutic doses, inhibit PON1 strongly by exhibiting different types of inhibition mechanisms.…”