A computational insight into acetylcholinesterase inhibitory activity of a new lichen depsidone

Acetylcholinesterase (AChE) inhibitors are yet the best drugs currently available for the management of Alzheimer's disease. The recent phytochemical investigation has led to the isolation of a new depsidone 1 with moderate AChE activity (1 mu g). This work was focused on its electronic properties analysed using commercially available programs. Both the active depsidone molecule 1 and galanthamine showed to have higher HOMO energies than the inactive depsidones 2-4, isolated from the same lichen species. However, the amino depsidone derivative 7, whose structure was proposed using computational approaches, is expected to be more active AChE inhibitor than the depsidone 1, due to the improved HOMO energy value. In addition, the molecular docking study indicated that the compound 7 has ability to make the well-known interactions of potent AChE inhibitors with the enzyme active site. The data presented herein support the design of novel AChE inhibitors based on the depsidone scaffold

Bioactive Indanes: Insight Into the Bioactivity of Iindane Dimers Related to the Lead Anti‐inflammatory Molecule PH46A

Objectives PH46A (1) demonstrates significant anti-inflammatory activity in phenotypic models but its mechanism and site of action have been elusive. Current study focused on the bioactivity of PH46 (2) and related novel indane dimers (6-10) to investigate the impact of changes in substitution and stereochemistry at the C-1 and C-2 positions of the PH46 (2) scaffold. Methods Cytotoxicity profiles of compounds were established using THP-1 macrophages and SW480 cells. Effects of the compounds were then evaluated at 10 μM using 5-lipoxygenase (LOX) and 15-LOX enzymes, and 5-LOX binding was evaluated in silico against NDGA, nitric oxide (NO) released from LPS-induced SW480 cells and cytokines in THP-1 macrophages (IL-6, IL-1b, TNF-a and IFN-c) and in SW480 cells (IL-8). Key findings PH46 (2) and 7 cause reduction in NO, inhibition of 5-LOX with high binding energy and no cytotoxicity effects in THP-1 macrophages and SW480 cell lines (up to 50 μM). The cytokine profiling of the series demonstrated inhibition of IL-6 and TNF-a in THP-1 macrophages together with IL-8 in SW480 cells. Conclusions The observed profile of cytokine modulation (IL-6/ TNF-a, IL-8) and inhibition of release of NO and 5-LOX may contribute to the in vivo effects demonstrated by indane dimers and PH46A (1) in murine models of colitis

Experimental and theoretical studies on tautomeric structures of a newly synthesized 2,2'(hydrazine-1,2-diylidenebis(propan-1-yl-1-ylidene)) diphenol

WOS: 000424631900022In the present study, a single crystal of a Schiff base, 2,2'(hydrazine-1,2-diylidenebis(propan-1-yl-1-ylidene)) diphenol, was synthesized. The structure of the synthesized crystal was confirmed by H-1 and C-13 NMR spectroscopic and X-ray diffraction analysis techniques. Experimental and theoretical studies were carried out on two tautomeric structures. It has been observed that the title compound studied can be in two different tautomeric forms, phenol-imine and keto-amine. Theoretical calculations have been performed to support experimental results. Accordingly, the geometric parameters of the compound were optimized by the density functional theory (DFT) method using the Gaussian 09 and Quantum Espresso (QE) packet program was used for periodic boundary conditions (PBC) studies. Furthermore, the compound was also tested for in vitro antifungal activity against Sclerotinia sclerotiorum, Alternaria solani, Fusarium oxysporum f. sp. lycopersici and Monilinia fructigena plant pathogens. Promising inhibition profiles were observed especially towards A. solani. Finally, molecular docking studies and post-docking procedure based on Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) were also carried out to get insight into the compound's binding interactions with the potential. Although theoretical calculations showed that the phenol-imine form was more stable, keto-amine form was predicted to have better binding affinity which was concluded to result from loss of rotational entropy in phenol-imine upon binding. The results obtained here from both experimental and computational methods might serve as a potential lead in the development of novel anti-fungal agents. (C) 2018 Elsevier B.V. All rights reserved.Research Centre of Ahi Evran University [PYO-MUH.4001.15.004]This study was supported financially by the Research Centre of Ahi Evran University (PYO-MUH.4001.15.004). In addition, the numerical calculations reported in this paper were partially performed at TUBITAK ULAKBIM, High Performance and Grid Computing Center (TRUBA resources)

Computer-aided drug design

Abstract Computer-Aided Drug Design tools are now an indispensable part of drug discovery that have made key contributions to the development of drugs. In this editorial, I briefly provide an overview of CADD emphasizing its potential and invite authors from academia and the pharmaceutical and biotechnology sector to present their research in this collection

Synthesis, molecular modeling, and biological evaluation of 4-[5-aryl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl] benzenesulfonamides toward acetylcholinesterase, carbonic anhydrase I and II enzymes

In this study, 4-[5-aryl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl] benzenesulfonamides were synthesized, and inhibition effects on AChE, hCA I, and hCA II were evaluated. K-i values of the compounds toward hCA I were in the range of 24.2 +/- 4.6-49.8 +/- 12.8nm, while they were in the range of 37.3 +/- 9.0-65.3 +/- 16.7nm toward hCA II. K-i values of the acetazolamide were 282.1 +/- 19.7nm and 103.60 +/- 27.6nm toward both isoenzymes, respectively. The compounds inhibited AChE with K-i in the range of 22.7 +/- 10.3-109.1 +/- 27.0nm, whereas the tacrine had K-i value of 66.5 +/- 13.8nm. Electronic structure calculations at M06-L/6-31+G(d,p)//AM1 level and molecular docking studies were also performed to enlighten inhibition mechanism and to support experimental findings. Results obtained from calculations of molecular properties showed that the compounds obey drug-likeness properties. The experimental and computational findings obtained in this study might be useful in the design of novel inhibitors against hCA I, hCA II, and AChE