Molecular dynamics simulations, molecular docking, and kinetics study of kaempferol interaction on Jack bean urease: Comparison of extended solvation model

Abstract

Since the urease enzyme creates gastric cancer, peptic ulcer, hepatic coma, and urinary stones in millions of people worldwide, it is essential to find strong inhibitors to help patients. Natural products are well known for their beneficial effects on health and efforts are being made to isolate the ingredients, the so-called flavonoids. Flavonoids are now considered as an indispensable component in a variety of nutraceutical, pharmaceutical, and cosmetic applications. Kaempferol (KPF) is an antioxidant found in many fruits and vegetables. Many reports have explained the significant effects of dietary KPF in reducing the risk of chronic diseases such as cancer, ischemia, stroke, and Parkinson's. The current study aimed at investigating the inhibitory impact of KPF on Jack bean urease (JBU) using molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations to confirm the results obtained from isothermal titration calorimetry (ITC), extended solvation model, and docking software. In addition, UV-VIS spectrophotometry was used to study the kinetics of urease inhibition. Calorimetric and spectrophotometric determinations of the kinetic parameters of this inhibition indicate the occurrence of a reversible and noncompetitive mode. Also, the docking and MD results indicated that the urease had well adapted to the kaempferol in the binding pocket, thereby forming a stable complex. Kaempferol displayed low binding energy during MMPBSA calculations. The inhibitory potential of kaempferol was confirmed by experimental and simulation data, but in vivo investigations are also recommended to validate our results.

Current Trends and Changes in Use of Membrane Molecular Dynamics Simulations within Academia and the Pharmaceutical Industry

“…Other association MDs, however. are more readily studied with only several extended unrestrained simulations for longer periods, from 400 nanoseconds to 5–10 microseconds [ 24 , 138 , 139 ]. Unrestrained longer simulations allow differences to be compared more effectively over medium time intervals.…”

“…The rapidity which is now being achieved with MD means a much greater combination of cross-discipline focal areas such as genetics, toxicology and immunology, to name a few [ 96 , 150 ]. Using toxicology as an example, the use of predefined membrane models for metabolites, toxins and cellular byproducts analysis with MD means these can be tested rapidly by simply introducing the new compounds [ 22 , 24 ]. This is akin to the testing of novel compounds mentioned previously, where several cellular membranes of interest are designed and maintained as a base model system.…”

“…The overall comparisons between atomistic or partial hybrid MD and wet lab show an extremely high level of homology, from kinetics to expected cellular or other function. In most cases where discrepancies exist, there was a lack of proper model creation in the MD itself, or problems in wet laboratory experiments [ 24 , 25 ]. Here, MD often serve as another form of cross checking of laboratory data.…”

Chymotrypsin, Urease Inhibitory and Antioxidant Activities of Malva neglecta Wallr.

“…38 Yanı sıra bitkideki bir diğer fenolik bileşik olan kemferolün de kuvvetli üreaz inhibitörü olduğu (IC50: 6.96 μM) göz önüne serilmiştir. 39,40 M. neglecta'da bulunduğu rapor edilen kumarik asit ve kafeik asidin 41 de üreaz ve kimotripsin inhibe edici aktivitesinin araştırıldığı çalışmada her iki bileşiğin de kimotripsini inhibe edici aktivitesinin olmadığı, orta derecede üreaz inhibe edici aktiviteye sahip oldukları (sırasıyla IC50 değerleri: 265.6 ve 428.2 μM) bildirilmiştir. 42 Bu verilerden hareketle bitkinin gösterdiği kimotripsin ve üreaz inhibitörü aktivitelerde kersetin ve kemferol gibi fenolik bileşiklerin sorumlu olabileceği akla gelmektedir Literatürde M. neglecta'nın antioksidan aktivitesine ilaveten toplam fenol ve flavonoit içeriğinin belirlendiği çalışmalar mevcuttur.…”