Pharmacophore mapping of the crucial mediators of acetylcholinesterase and butyrylcholinesterase dual inhibition in Alzheimer's disease.

Optimization and re-optimization of bioactive molecules using in silico methods have found application in the design of more active ones. Herein, we applied a pharmacophore modeling approach to screen potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) aimed at Alzheimer's disease (AD) treatment. The investigation entails molecular dynamics simulation, docking, pharmacophore modeling, drug-like screening, and binding energy analysis. We prepared a pharmacophore model from approved inhibitors of AChE and BuChE to predict the crucial moieties required for optimum molecular interaction with these proteins. The obtained pharmacophore model, used for database screening via some critical criteria, showed 229 hit molecules. Further analyses showed 42 likely dual inhibitors of AChE/BuChE with drug-like and pharmacokinetics properties the same as the approved cholinesterase inhibitors. Finally, we identified 14 dual molecules with improved potentials over the existing inhibitors and simulated ZINC92385797 bound to human AChE and BuChE structure after noticing that these 14 molecules are similar. The selected compound maintained relative stability at the active sites of both proteins over 120 ns simulation. Our integrated protocols showed the pertinent recipes of anti-AD drug design through the in silico pipeline.

Allostery Inhibition of BACE1 by Psychotic and Meroterpenoid Drugs in Alzheimer's Disease Therapy.

In over a century since its discovery, Alzheimer's disease (AD) has continued to be a global health concern due to its incurable nature and overwhelming increase among older people. In this paper, we give an overview of the efforts of researchers towards identifying potent BACE1 exosite-binding antibodies and allosteric inhibitors. Herein, we apply computer-aided drug design (CADD) methods to unravel the interactions of some proposed psychotic and meroterpenoid BACE1 allosteric site inhibitors. This study is aimed at validating the allosteric potentials of these selected compounds targeted at BACE1 inhibition. Molecular docking, molecular dynamic (MD) simulations, and post-MD analyses are carried out on these selected compounds, which have been experimentally proven to exhibit allosteric inhibition on BACE1. The SwissDock software enabled us to identify more than five druggable pockets on the BACE1 structural surface using docking. Besides the active site region, a melatonin derivative (compound 1) previously proposed as a BACE1 allostery inhibitor showed appreciable stability at eight different subsites on BACE1. Refinement with molecular dynamic (MD) simulations shows that the identified non-catalytic sites are potential allostery sites for compound 1. The allostery and binding mechanism of the selected potent inhibitors show that the smaller the molecule, the easier the attachment to several enzyme regions. This finding hereby establishes that most of these selected compounds failed to exhibit strong allosteric binding with BACE1 except for compound 1. We hereby suggest that further studies and additional identification/validation of other BACE1 allosteric compounds be done. Furthermore, this additional allosteric site investigation will help in reducing the associated challenges with designing BACE1 inhibitors while exploring the opportunities in the design of allosteric BACE1 inhibitors.

Thermogravimetric Analysis of Modified Montmorillonite Clay for Mycotoxin Decontamination in Cereal Grains.

Thermogravimetric analysis (TGA) was carried out to study the stability of nanoformulations used for the decontamination of mycotoxins. The TGA patterns of the nanoformulations from montmorillonite clay and Cymbopogon citratus (lemongrass) extracts were assessed with temperature ranging from ambient (20°C) to 1000°C. The various nanoformulations studied included unmodified montmorillonite clay (Mont), montmorillonite washed with sodium chloride (Mont-Na), montmorillonite mixed with lemongrass essential oil (Mont-LGEO), and montmorillonite mixed with an equal quantity of lemongrass powder (Mont-LGP). There was no significant difference in the median of the various nanoformulations within 4 weeks at p < 0.05 using the Kruskal-Wallis nonparametric test. For the TGA, the first degradation for montmorillonite clay and the nanoformulations occurred at a temperature between 80 and 101°C and was attributed to the loss of lattice water outside the coordination sphere with a range of 3.5-6.5% weight loss. The second degradation occurred within the temperature of 338 to 344°C, and the third, at a temperature between 640 and 668°C for Mont and the formulations of Mont-Na, Mont-LGEO, and Mont-LGP. There were strong similarities in the degradation patterns of Mont and Mont-Na with the minimum difference being the relatively higher weight loss of the sodium-exchanged cation for Mont-Na at the third degradation step. Hence, the order of stability from the most resistant to the least resistant to degradation is as follows: Mont-LGEO ≥ Mont-Na ≥ Mont ≥ Mont-LGP.

Deep eutectic solvent as an efficient modifier of low-cost adsorbent for the removal of pharmaceuticals and dye.

Waste from biomass was used to prepare a low-cost biochar-clay hybrid adsorbent. The hybrid adsorbent was synthesised by combining Kaolin with biomass (Vitex doniana), thereafter, modified with Deep Eutectic Solvent (DES). The materials were characterised using scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectrometry (FTIR), Thermal gravimetric analysis (TGA), and Brunauer-Emmett-Teller (BET), also, pHpzc of the materials were studied. The resultant adsorbents were used for both column and batch adsorption of organic pollutants; dye (Acid Blue 74; AB74) and pharmaceuticals (ciprofloxacin; CIP and acetaminophen; ACTE). Column adsorption capacity, effect of pollutant concentration and effect of flow rate were studied, also, the column was modelled using Thomas, Yoon-Nelson and Adams-Bohart model. Furthermore, batch adsorption experiments were performed, effect of change in pH, time, dose and concentration were studied. Batch adsorption data were fitted with isotherm and kinetic models. The experiment showed tremendous increase in adsorption capacity when the hybrid adsorbent (HYD) was modified with DES (HYD-DES). Acid Blue 74 on HYD-DES has the highest column sorption capacity followed by ciprofloxacin and acetaminophen. Adsorption was favoured at pH range of 2-10 for both AB74 and ACTE as there is no significant changes in the % removal performance, while adsorption was best at pH 6 and above for CIP. AB74 and CIP are best described by Langmuir isotherm, whereas ACTE adsorption was best explained by Freundlich isotherm equilibrium. The DES modified HYD has shown it can be effectively utilised as possible adsorbent for adsorbing organic dyes and pharmaceuticals.

Brief bibliometric analysis of "ionic liquid" applications and its review as a substitute for common adsorbent modifier for the adsorption of organic pollutants.

The importance of improving adsorbent's adsorption efficiency in organic pollutants has been reported by many researchers. Surfactant-based modified adsorbents were a tasteful choice. As a result, the use of surfactants as a modifier for removing organic pollutants has shown to play a very big role in enhancing the adsorption efficiency of different materials. Ionic liquids are receiving extensive interest as green multipurpose compounds, primarily as a replacement for traditional chemicals that are used in many chemical processes. This work gives a brief bibliometric analysis of application of ionic liquid from 1930 to 2017, documents were collected from Scopus database and keywords from the abstracts and titles were analyzed using VOSviewer software. Furthermore, the work presents a review of conventionally known surfactants and the recent likelihood of ionic liquids for modifying adsorbents for adsorption of organic pollutants. Over the period of years between 1930 and 2017, 13,144 documents were published on the application of ionic liquids. VOSviewer software further confirms that adsorption is one of the leading areas in applications of ionic liquids. Review also showed that ionic liquid is a good modifier of adsorbents.

Theoretical and experimental adsorption studies of sulfamethoxazole and ketoprofen on synthesized ionic liquids modified CNTs.

The adsorption of sulfamethoxazole (SMZ) and ketoprofen (KET) using carbon nanotubes (CNTs) and CNTs modified with ionic liquids (ILs) was investigated. Two ionic liquids (1-benzyl, 3-hexyl imidazolium, IL1 and 1-benzyl, 3-decahexyl imidazolium, IL2) were synthesized, and characterized by nuclear magnetic resonance (1H and 13C NMR) and high resolution-mass spectrometry (HR-MS). CNTs and modified CNTs were characterized using FT-IR, X-ray diffraction (XRD), surface area and porosity analysis, thermal gravimetric analysis (TGA), Zeta potential, Raman and scanning electron microscopy (SEM). Kinetics, isotherm and computational studies were carried out to determine the efficiency and adsorption mechanism of SMZ and KET on modified CNTs. A density functional theory (DFT) method was applied to shed more light on the interactions between the pharmaceutical compounds and the adsorbents at the molecular level. The effects of adsorbent dosage, concentration, solution pH, energetics and contact time of SMZ and KET on the adsorption process were investigated. The adsorption of SMZ and KET on CNTs and modified CNTs were pH dependent, and adsorption was best described by pseudo-second-order kinetics and the Freundlich adsorption isotherm. Ionic liquid modified CNTs showed improved adsorption capacities compared to the unmodified ones for both SMZ and KET, which is in line with the computational results showing performance order; CNT+KET/SMZ < CNT-ILs+SMZ < CNT-ILs+KET.

Ni2+ and Cu2+ complexes of N-(2,6-dichlorophenyl)-N-mesityl formamidine dithiocarbamate structural and functional properties as CYP3A4 potential substrates.

Metal compounds continued to attract diverse applications due to their malleability in several capacities. In this study, we present our findings on the crystal structures and functional properties of Ni2+ and Cu2+ complexes of N'-(2,6-dichlorophenyl)-N-mesitylformamidine dithiocarbamate (L) comprising [Ni-(L)2] (1) and [Cu-(L)2] (2) with a four-coordinate metal center. We established the two complex structures through 1H and 13C nuclear magnetic resonance (NMR), elemental, and single-crystal X-ray analysis. The analyses showed that the two complexes are isomorphous, having P21/c as a space group and a unit-cell similarity index (π) of 0.002. The two complexes conform to a distorted square planar geometry around the metal centers. The calculated and experimental data, including bond lengths, angles, and NMR values, are similar. Hirshfeld surface analysis revealed the variational contribution of the different types of intermolecular contacts driven by the crystal lattice of the two solvated complexes. Our knowledge of the potential biological implication of these structures enabled us to probe the compounds as prospective CYP3A4 inhibitors. This approach mimics current trends in pharmaceutical design and biomedicine by incorporating potentially active molecules into various media to predict their biological efficacies. The simulations show appreciable binding of compounds 1 and 2 to CYP3A4 with average interaction energies of -97 and -87 kcal/mol, respectively. The protein attains at least five conformational states in the three studied models using a Gaussian Mixture Model-based clustering and free energy prediction. Electric field analysis shows the crucial residues to substrate binding at the active site, enabling CYP3A4 structure to function prediction. The predicted inhibition with these Ni2+ and Cu2+ complexes indicates that CYP3A4 overexpression in a diseased state like cancer would reduce, thereby increasing the chemotherapeutic compounds' shelf-lives for adsorption. This multidimensional study addresses various aspects of molecular metal electronics, including their application as substrate-mimicking inhibitors. The outcome would enable further research on bio-metal compounds of critical potential.

Alzheimer's Disease and ß-secretase Inhibition: An Update with a Focus on Computer-aided Inhibitor Design.

INTRODUCTION: Alzheimer's disease (AD) is an intensifying neurodegenerative illness due to its irreversible nature. Identification of ß-site Amyloid Precursor Protein (APP) cleaving en-zyme1 (BACE1) has been a significant medicinal focus towards AD treatment, and this has opened ground for several investigations. Despite the numerous works in this direction, no BACE1 inhibitor has made it to the final approval stage as an anti-AD drug. METHODS: We provide an introductory background of the subject with a general overview of the pathogenesis of AD. The review features BACE1 inhibitor design and development with a focus on some clinical trials and discontinued drugs. Using the topical keywords BACE1, inhibitor design, and computational/theoretical study in the Web of Science and Scopus database, we retrieved over 49 relevant articles. The search years are from 2010 and 2020, with analysis conducted from May 2020 to March 2021. RESULTS AND DISCUSSION: Researchers have employed computational methodologies to unravel po-tential BACE1 inhibitors with a significant outcome. The most used computer-aided approach in BACE1 inhibitor design and binding/interaction studies are pharmacophore development, quantita-tive structure-activity relationship (QSAR), virtual screening, docking, and molecular dynamics (MD) simulations. These methods, plus more advanced ones including quantum mechan-ics/molecular mechanics (QM/MM) and QM, have proven substantial in the computational frame-work for BACE1 inhibitor design. Computational chemists have embraced the incorporation of in vitro assay to provide insight into the inhibition performance of identified molecules with potential inhibition towards BACE1. Significant IC50 values up to 50 nM, better than clinical trial com-pounds, are available in the literature. CONCLUSION: The continuous failure of potent BACE1 inhibitors at clinical trials is attracting many queries prompting researchers to investigate newer concepts necessary for effective inhibitor de-sign. The considered properties for efficient BACE1 inhibitor design seem enormous and require thorough scrutiny. Lately, researchers noticed that besides appreciable binding affinity and Blood-Brain Barrier (BBB) permeation, BACE1 inhibitor must show low or no affinity for permeability-glycoprotein. Computational modeling methods have profound applications in drug discovery strat-egies. With the volume of recent in silico studies on BACE1 inhibition, the prospect of identifying potent molecules that would reach the approved level is feasible. Investigators should try pushing many of the identified BACE1 compounds with significant anti-AD properties to preclinical and clinical trial stages. We also advise computational research on allosteric inhibitor design, exosite modeling, and multisite inhibition of BACE1. These alternatives might be a solution to BACE1 drug discovery in AD therapy.

Engineered Geomedia Kaolin Clay-Reduced Graphene Oxide-Polymer Composite for the Remediation of Olaquindox from Water.

Globally, there is an upsurge in the use of unregulated veterinary pharmaceuticals with enhanced release into the environment, resulting in water pollution, which is difficult to remediate. To address this issue, we synthesized and characterized highly hydrophobic three-dimensional ordered engineered geomedia with multiple channels. Kaolin clay (K) was functionalized with either graphene oxide (GO) synthesized via Tour's method or reduced GO in situ with covalently linked methoxyether polyethylene glycol (GO-PEG) using a simple and easily scalable amidation reaction. This was done to enhance the adsorption of olaquindox, a veterinary antibiotic. The X-ray diffraction profile confirmed the grafting of GO and GO-PEG to kaolin. Morphological analysis revealed the architecture of thin films of GO/GO-PEG grafted on the kaolin surface with extensive porosity. Energy-dispersive X-ray mapping, infra-red spectra, and elemental analysis confirmed the successful synthesis of the engineered geomedia composite of K, GO/rGO, and PEG (KrGO-PEG). Due to multiple surface functional groups of polyamide and amido-carbonic groups on the KrGO-PEG composite, it was suitable for olaquindox adsorption. In batch sorption studies of 0.5XKrO-PEG, the effect of pH (2-10) was negligible but with fast equilibrium time (2-1440 min) at 30 min, while the kinetics and equilibrium data suited the pseudo-second order and Langmuir models, respectively. The maximum adsorption value obtained for the composite was 59.5 mg/g; the higher the GO content, the higher the adsorption. The sorption mechanism was majorly through hydrophobic and π-π interactions. Regenerated/reused adsorbents after 4 cycles had the same efficacy in remediating olaquindox from simulated/real water.

Design of New Schiff-Base Copper(II) Complexes: Synthesis, Crystal Structures, DFT Study, and Binding Potency toward Cytochrome P450 3A4.

We report the synthesis and crystal structures of three new copper(II) Schiff-base complexes. The complexes have been characterized by elemental analysis and Fourier transform infrared (FT-IR) and UV-visible spectroscopies. The X-ray diffraction (XRD) analysis reveals that complexes 1 and 3 crystallize in a monoclinic space group C2/c and 2 in a triclinic space group P1̅, each adopting a square planar geometry around the metal center. We use a density functional theory method to explore the quantum chemical properties of these complexes. The calculation proceeds with the three-dimensional (3D) crystal structure characterization of the complexes in which the calculated IR and UV-vis values are comparable to the experimental results. Charge distribution and molecular orbital analyses enabled quantum chemical property prediction of these complexes. We study the drug-likeness properties and binding potentials of the synthesized complexes. The in silico outcome showed that they could serve as permeability-glycoprotein (P-gp) and different cytochrome P450 substrates. Our calculations showed that the complexes significantly bind to cytochrome P450 3A4.

Covalently linked graphene oxide/reduced graphene oxide-methoxylether polyethylene glycol functionalised silica for scavenging of estrogen: Adsorption performance and mechanism.

Water pollution by pharmaceuticals is a global issue and its remediation is important. To overcome this, we synthesised super hydrophobic nanoporous 3-dimensional ordered nanomaterials with multi-functional binding chemistry for highly efficient adsorption of estrogen (17ß-estradiol). Graphene oxide (GO) was synthesised via Tours method and methoxylether polyethylene glycol (mPEG) was covalently introduced onto GO surface via facile amidation mild process to give GO-mPEG. GO-mPEG was anchored on nanoporous SBA-15 and homogenously reduced in-situ to SBA-rGO-mPEG. XRD analysis confirmed successful synthesis of SBA-15 and cross-linked GO/rGO-mPEG on SBA-15 surface. Image analysis revealed the architecture of SBA-15 as porous 3-dimensional silica network and presence of interwoven/crosslinked thin-films of GO-mPEG on SBA-15 surface. EDX mapping/elemental analysis showed expected elements were present. FTIR and textural analysis revealed the presence of different functional groups and high surface area as well as porosity, respectively. Optimal molar ratio experiments showed that 0.5SBA-rGO-mPEG had the highest sorption capacity. The relatively large surface area, 3-dimensional nanoprous silica structure and excess of polyamide/amido-carbonic functional groups on nanocomposites were suited for adsorption of 17ß-estradiol. Equilibrium time was 30 min and effect of pH on adsorption was negligible. Sorption kinetic process of SBA-rGO-mPEG suited the pseudo-second-order model and equilibrium data fitted both Freundlich and Langmuir models. Qm values of 57.1, 78.5, 102.6 and 192.3 mg/g was recorded for SBA-GO, 0.1SBA-rGO-mPEG, 0.25SBA-rGO-mPEG and 0.5SBA-rGO-mPEG, respectively. H-bond, hydrophobic and π-π interactions were the sorption mechanism of SBA-rGO-mPEG after detailed analysis of data. Adsorbents was regenerated/re-used after 4 cycles with high remediation from environmental/real water samples.

Density functional theory study of gold(III)-dithiocarbamate complexes with characteristic anticancer potentials.

The application of gold as drug candidate dated back to 2500 BC and its relevance in medicine became more appealing following 1985 FDA approval of ingested Auranofin for the treatment of rheumatoid arthritis. In this study, we have provided a density functional theory (DFT) study of some gold(III)-dithiocarbamate complexes with characteristic anticancer potentials. DFT calculation of the reactivity and selectivity properties of these complexes with an enzyme template of thioredoxin reductase (TrxR) was carried out. The investigation proceeds with theoretical characterization of the selected compounds through spectroscopic analyses. IR and UV-vis analyses were carried out and the calculated values are comparable to experimental results. NMR assignment was determined for the gold compounds and the estimated theoretical chemical shift values agree with available experimental data from literature. The obtained DFT-based chemical parameters proved to be significant in evaluating the selectivity, reactivity and stability of the gold(III) complexes as potential anticancer moieties, specifically against TrxR. Calculated binding free energy gave similar order with the available in vitro inhibition profile of these gold(III)-dithiocarbamate complexes against TrxR. The outcome of this DFT study could serve as a useful guide towards future design of new and potent anticancer drug candidate. The investigated chemical reactivity properties could be considered and applied to a wide range of bioactive compounds and enzyme-inhibitor systems.

Antifouling Properties of Silver-Zinc Oxide Polyamide Thin Film Composite Membrane and Rejection of 2-Chlorophenol and 2,4-Dichlorophenol.

The silver-zinc oxide (Ag-ZnO) polyamide thin film composite (PA-TFC) membrane was prepared by interfacial polymerization. The Ag-ZnO/PA-TFC membrane was characterized by attenuated total reflectance fourier-transform infrared spectroscopy (ATR-FTIR) for polyamide functional groups and contact angle for surface hydrophilicity. The Ag-ZnO/PA-TFC membrane was further characterized by Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) for morphology and surface roughness, respectively. The performance of the fabricated membrane was investigated using pure water flux, permeability, rejection, flux recovery, and fouling resistance using low molecular weight organic pollutants, 2-chlorophenol (2-CP) and 2,4-dichlorophenol (2,4-DCP). The results were compared to the neat (PA-TFC) membrane. It was observed that incorporation of Ag-ZnO nanocomposites into the PA-TFC membrane improved hydrophilicity, permeation, rejection, and fouling resistance properties of the membrane. The contact angle decreased from 62.8° to 54° for PA-TFC and the Ag-ZnO/PA-TFC membrane, respectively. The presence of Ag-ZnO enhanced permeability of the membrane from 0.9 (Lm-2h-1bar-1) to 1.9 (Lm-2h-1bar-1). Modification of the membrane with Ag-ZnO further showed an enhanced rejection of 2-CP and 2,4-DCP from 43% to 80% and 58% to 85%, respectively. The 2,4-DCP molecules were rejected more than 2-CP due to enhanced repulsive forces from the extra Cl ion. A high flux recovery of about 95% was achieved for the modified membrane compared to 64% for the neat membrane. The improved flux recovery was an indication of enhanced antifouling propensity.

Decontamination of T-2 Toxin in Maize by Modified Montmorillonite Clay.

Montmorillonite clay has a wide range of applications, one of which includes the binding of mycotoxins in foods and feeds through adsorption. T-2 toxin, produced by some Fusarium, Myrothecium, and Stachybotrys species, causes dystrophy in the brain, heart, and kidney. Various formulations that include lemongrass essential oil-modified montmorillonite clay (LGEO-MMT), lemongrass powder (LGP), montmorillonite clay washed with 1 mM NaCl (Na-MMT), montmorillonite clay (MMT), and lemongrass powder mixed with montmorillonite clay (LGP-MMT) were applied to maize at concentrations of 8% and 12% and stored for a period of one month at 30 °C. Unmodified montmorillonite clay and LGP served as the negative controls alongside untreated maize. Fourier Transform Infrared (FTIR) spectra of the various treatments showed the major functional groups as Si-O and -OH. All treatment formulations were effective in the decontamination of T-2 toxin in maize. Accordingly, it was revealed that the inclusion of Na-MMT in maize at a concentration of 8% was most effective in decontaminating T-2 toxin by 66% in maize followed by LGP-MMT at 12% inclusion level recording a 56% decontamination of T-2 toxin in maize (p = 0.05). Montmorillonite clay can be effectively modified with plant extracts for the decontamination of T-2 toxin.