A novel isatin Schiff based cerium complex: synthesis, characterization, antimicrobial activity and molecular docking studies.

In this work, a novel isatin-Schiff base L2 had been synthesized through a simple reaction between isatin and 2-amino-5-methylthio-1,3,4-thiadiazole. The produced Schiff base L2 was then subjected to a hydrothermal reaction with cerium chloride to produce the cerium (III)-Schiff base complex C2. Several spectroscopic methods, including mass spectra, FT-IR, elemental analysis, UV-vis, 13C-NMR, 1H-NMR, Thermogravimetric Analysis, HR-TEM, and FE-SEM/EDX, were used to completely characterize the produced L2 and C2. A computer simulation was performed using the MOE software program to find out the probable biological resistance of studied compounds against the proteins in some types of bacteria or fungi. To investigate the interaction between the ligand and its complex, we conducted molecular docking simulations using the molecular operating environment (MOE). The docking simulation findings revealed that the complex displayed greater efficacy and demonstrated a stronger affinity for Avr2 effector protein from the fungal plant pathogen Fusarium oxysporum (code 5OD4) than the original ligand. The antibacterial activity of the ligand and its Ce3+ complex were applied in vitro tests against different microorganism. The study showed that the complex was found to be more effective than the ligand.

Synthesis and Biological Evaluation of 2-Azolylmethylene-3-(2H)-benzofuranone Derivatives as Potent Monoamine Oxidases Inhibitors.

A series of 2-azolylmethylene-3-(2H)-benzofuranone derivatives, 2-indolylmethylene-3-(2H)-benzofuranone and 2-pyrrolylmethylene-3-(2H)-benzofuranone derivatives, were synthesized, and their monoamine oxidase (MAO) A and B inhibitory activities were evaluated. Compounds 1b, 3b, 6b, 7b, and 10b showed strong inhibitory activity against MAO-A, and compound 3b showed the highest potency and selectivity, with an IC50 value of 21 nM and a MAO-A selectivity index of 48. Compounds 3c, 4c, 9a, 9c, 10c, 11a, and 11c showed strong inhibitory activity against MAO-B, and compound 4c showed the highest potency and selectivity, with an IC50 value of 16 nM and a MAO-B selectivity index of >1100. Further analysis of these compounds indicated that compound 3b for MAO-A and compound 4c for MAO-B were competitive inhibitors, with Ki values of 10 and 6.1 nM, respectively. Furthermore, computational analyses, such as quantitative structure-activity relationship (QSAR) analysis of the 2-azolylmethylene-3-(2H)-benzofuranone derivatives conducting their pIC50 values with the Molecular Operating Environment (MOE) and Mordred, and molecular docking analysis using MOE-Dock supported that the 2-azolylmethylene-3-(2H)-benzofuranone derivatives are a privileged scaffold for the design and development of novel MAO inhibitors.

Screening and identification of potential MERS-CoV papain-like protease (PLpro) inhibitors; Steady-state kinetic and Molecular dynamic studies.

MERS-CoV belongs to the coronavirus group. Recent years have seen a rash of coronavirus epidemics. In June 2012, MERS-CoV was discovered in the Kingdom of Saudi Arabia, with 2,591 MERSA cases confirmed by lab tests by the end of August 2022 and 894 deaths at a case-fatality ratio (CFR) of 34.5% documented worldwide. Saudi Arabia reported the majority of these cases, with 2,184 cases and 813 deaths (CFR: 37.2%), necessitating a thorough understanding of the molecular machinery of MERS-CoV. To develop antiviral medicines, illustrative investigation of the protein in coronavirus subunits are required to increase our understanding of the subject. In this study, recombinant expression and purification of MERS-CoV (PLpro), a primary goal for the development of 22 new inhibitors, were completed using a high throughput screening methodology that employed fragment-based libraries in conjunction with structure-based virtual screening. Compounds 2, 7, and 20, showed significant biological activity. Moreover, a docking analysis revealed that the three compounds had favorable binding mood and binding free energy. Molecular dynamic simulation demonstrated the stability of compound 2 (2-((Benzimidazol-2-yl) thio)-1-arylethan-1-ones) the strongest inhibitory activity against the PLpro enzyme. In addition, disubstitutions at the meta and para locations are the only substitutions that may boost the inhibitory action against PLpro. Compound 2 was chosen as a MERS-CoV PLpro inhibitor after passing absorption, distribution, metabolism, and excretion studies; however, further investigations are required.

Discovery of Phenylcarbamoylazinane-1,2,4-Triazole Amides Derivatives as the Potential Inhibitors of Aldo-Keto Reductases (AKR1B1 & AKRB10): Potential Lead Molecules for Treatment of Colon Cancer.

Both members of the aldo-keto reductases (AKRs) family, AKR1B1 and AKR1B10, are over-expressed in various type of cancer, making them potential targets for inflammation-mediated cancers such as colon, lung, breast, and prostate cancers. This is the first comprehensive study which focused on the identification of phenylcarbamoylazinane-1, 2,4-triazole amides (7a−o) as the inhibitors of aldo-keto reductases (AKR1B1, AKR1B10) via detailed computational analysis. Firstly, the stability and reactivity of compounds were determined by using the Guassian09 programme in which the density functional theory (DFT) calculations were performed by using the B3LYP/SVP level. Among all the derivatives, the 7d, 7e, 7f, 7h, 7j, 7k, and 7m were found chemically reactive. Then the binding interactions of the optimized compounds within the active pocket of the selected targets were carried out by using molecular docking software: AutoDock tools and Molecular operation environment (MOE) software, and during analysis, the Autodock (academic software) results were found to be reproducible, suggesting this software is best over the MOE (commercial software). The results were found in correlation with the DFT results, suggesting 7d as the best inhibitor of AKR1B1 with the energy value of −49.40 kJ/mol and 7f as the best inhibitor of AKR1B10 with the energy value of −52.84 kJ/mol. The other potent compounds also showed comparable binding energies. The best inhibitors of both targets were validated by the molecular dynamics simulation studies where the root mean square value of <2 along with the other physicochemical properties, hydrogen bond interactions, and binding energies were observed. Furthermore, the anticancer potential of the potent compounds was confirmed by cell viability (MTT) assay. The studied compounds fall into the category of drug-like properties and also supported by physicochemical and pharmacological ADMET properties. It can be suggested that the further synthesis of derivatives of 7d and 7f may lead to the potential drug-like molecules for the treatment of colon cancer associated with the aberrant expression of either AKR1B1 or AKR1B10 and other associated malignancies.

Synthesis and biological evaluation of 3-styrylchromone derivatives as selective monoamine oxidase B inhibitors.

A series of 3-styrylchromone derivatives was synthesized and evaluated for monoamine oxidase (MAO) A and B inhibitory activities. Most of all derivatives inhibited MAO-B selectively, except compound 21. Compound 19, which had a methoxy group at R2 on the chromone ring and chlorine at R4 on phenyl ring, potently inhibited MAO-B, with an IC50 value of 2.2 nM. Compound 1 showed the highest MAO-B selectivity, with a selectivity index of >3700. Further analysis of these compounds indicated that compounds 1 and 19 were reversible and mixed-type MAO-B inhibitors, suggesting that their mode of action may be through tight-binding inhibition to MAO-B. Quantitative structure-activity relationship (QSAR) analyses of the 3-styrylchromone derivatives were conducted using their pIC50 values, through Molecular Operating Environment (MOE) and Dragon. There were 1796 descriptors of MAO-B inhibitory activity, which showed significant correlations (P < 0.05). Further investigation of the 3-styrylchromone structures as useful scaffolds was performed through three-dimensional-QSAR studies using AutoGPA, which is based on the molecular field analysis algorithm using MOE. The MAO-B inhibitory activity model constructed using pIC50 value index exhibited a determination coefficients (R2) of 0.972 and a Leave-One-Out cross-validated determination coefficients (Q2) of 0.914. These data suggest that the 3-styrylchromone derivatives assessed herein may be suitable for the design and development of novel MAO inhibitors.

Synthesis, characterization, antibacterial evaluation, 2D-QSAR modeling and molecular docking studies for benzocaine derivatives.

Possible application of incorporating a well-known drug (benzocaine) with cyanoacetamide function to get a powerful synthon ethyl 4-cyanoacetamido benzoate. This synthetic intermediate was used as a precursor for the synthesis of triazine, pyridone, thiazolidinone, thiazole and thiophene scaffolds containing the benzocaine core. Facile coupling, Michael addition, condensation and nucleophilic attack reactions were used to synthesize our targets. The structural features of the synthesized scaffolds were characterized using IR, 1H NMR, 13C NMR and mass spectroscopy. The antibacterial activities against Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) were evaluated using ampicillin as a reference drug. DNA/methyl-green colorimetric assay of the DNA-binding compounds was also performed. Theoretical studies of the newly synthesized compounds based on molecular docking and QSAR study were conducted. The molecular docking studies were screened by MOE software for the more potent antibacterial agent 28b and each native ligand against four of S. aureus proteins 1jij, 2xct, 2w9s and 3t07.

Isoform-Selective NFAT Inhibitor: Potential Usefulness and Development.

Nuclear factor of activated T cells (NFAT), which is the pharmacological target of immunosuppressants cyclosporine and tacrolimus, has been shown to play an important role not only in T cells (immune system), from which their name is derived, but also in many biological events. Therefore, functional and/or structural abnormalities of NFAT are linked to the pathogenesis of diseases in various organs. The NFAT protein family consists of five isoforms, and each isoform performs diverse functions and has unique expression patterns in the target tissues. This diversity has made it difficult to obtain ideal pharmacological output for immunosuppressants that inhibit the activity of almost all NFAT family members, causing serious and wide-ranging side effects. Moreover, it remains unclear whether isoform-selective NFAT regulation can be achieved by targeting the structural differences among NFAT isoforms and whether this strategy can lead to the development of better drugs than the existing ones. This review summarizes the role of the NFAT family members in biological events, including the development of various diseases, as well as the usefulness of and problems associated with NFAT-targeting therapies, including those dependent on current immunosuppressants. Finally, we propose a novel therapeutic strategy based on the molecular mechanisms that enable selective regulation of specific NFAT isoforms.

2-Styrylchromone derivatives as potent and selective monoamine oxidase B inhibitors.

A series of eighteen 2-styrylchromone derivatives (see Chart 1) were synthesized and evaluated for their monoamine oxidase (MAO) A and B inhibitory activities. Many of the derivatives inhibited MAO-B comparable to pargyline (a positive control), and most of them inhibited MAO-B selectively. Of the eighteen derivatives, compound 9 having methoxy group at R1 and chlorine at R4 showed both the best MAO-B inhibitory activity (IC50 = 17 ±â€¯2.4 nM) and the best MAO-B selectivity (IC50 for MAO-A/IC50 for MAO-B = 1500). The mode of inhibition of compound 9 against MAO-B was competitive and reversible. Quantitative structure-activity relationship (QSAR) analyses of the 2-styrylchromone derivatives were conducted using their pIC50 values with the use of Molecular Operating Environment (MOE) and Dragon, demonstrating that the descriptors of MAO-B inhibitory activity and MAO-B selectivity were 1734 and 121, respectively, that showed significant correlations (P < 0.05). We then examined the 2-styrylchromone structures as useful scaffolds through three-dimensional-QSAR studies using AutoGPA, which is based on the molecular field analysis algorithm using MOE. The model using pIC50 value indexes for MAO-B exhibited a determination coefficient (R2) of 0.873 as well as a Leave-One-Out cross-validated determination coefficient (Q2) of 0.675. These data suggested that the 2-styrylchromone structure might be a useful scaffold for the design and development of novel MAO-B inhibitors.

Salting-out thin-layer chromatography and computational analysis of some oral hypoglycemic drugs.

A quantitative structure-retention relationship study of some oral hypoglycemic drugs was carried out using a salting-out thin-layer chromatographic technique. Aqueous solution of ammonium sulfate and acetonitrile was used as a mobile phase. It was established that the applied mobile phase has different effects on retention of the studied oral antidiabetic drugs. The factors that affect the salting-out process were determined. In this study a good correlation between the structures of the investigated drugs with the retention data and molecular descriptors was established throughout computational analysis and using molecular operating environment software, focusing on octanol/water partition coefficient, molar refractivity, total hydrophobic surface area, hydrophobic volume, Van der Waals energy and solvation energy. Quantitative structure-retention relationship modeling for the separation of the investigated drugs was carried out, validated and evaluated.

An Integrated Computational Approaches for Designing of Potential Piperidine based Inhibitors of Alzheimer Disease by Targeting Cholinesterase and Monoamine Oxidases Isoenzymes.

The study aimed to evaluate the potential of piperidine-based 2H chromen-2-one derivatives against targeted enzymes, i.e., cholinesterase's and monoamine oxidase enzymes. The compounds were divided into three groups, i.e., 4a-m ((3,4-dimethyl-7-((1-methylpiperidin-4-yl)oxy)-2H-chromen-2-one derivatives), 5a-e (3,4-dimethyl-7-((1-methypipridin-3-yl)methoxy)-2H-chromen-2-one derivatives), and 7a-b (7-(3-(3,4-dihydroisoquinolin-2(1H)-yl)propoxy)-3,4-dimethyl-2H-chromen-2-one derivatives) with slight difference in the basic structure. The comprehensive computational investigations were conducted including density functional theories studies (DFTs), 2D-QSAR studies, molecular docking, and molecular dynamics simulations. The QSAR equation revealed that the activity of selected chromen-2-one-based piperidine derivatives is being affected by the six descriptors, i.e., Nitrogens Count, SdssCcount, SssOE-Index, T-2-2-7, ChiV6chain, and SssCH2E-Index. These descriptor values were further used for the preparation of chromen-2-one based piperidine derivatives. Based on this, 83 new derivatives were created from 7 selected parent compounds. The QSAR model predicted their IC50 values, with compound 4 k and 4kk as the most potent multi-targeted derivative. Molecular docking results exhibited these compounds as the best inhibitors; however, 4kk exhibited greater activity than the parent compounds. The results were further validated by molecular dynamic simulation studies along with the suitable physicochemical properties. These results prove to be an essential guide for the further design and development of new piperidine based chromen-2-one derivatives having better activity against neurodegenerative disorder.

Design, synthesis and biological evaluation of novel triaryl (Z)-olefins as tamoxifen analogues.

Tamoxifen (TAM) is used for the treatment and prevention of estrogen receptor positive breast cancer. However, the limited activity, toxicity and the development of resistance raised the current need for new potent nontoxic antiestrogen. Six novel TAM analogues 5a-f were synthesized using McMurry olefination reaction. Replacement of the dimethylamino group in TAM by piperidino, piperazino or N-methyl piperazino, substituting the phenyl ring with florine atom at p-position and changing the ethyl group by methyl, afforded compounds showing comparable activity to TAM (1). Compounds 5c and 5e showed significant increase in antiproliferative activity in two breast cancer cell lines (MCF-7 and MDA-MB-231) compared to tamoxifen, while other compounds showed similar activity. The increased anticancer activity of compounds 5c and 5e was attributed to their ability to induce ER-independent cell death.

Tackling the conformational sampling of larger flexible compounds and macrocycles in pharmacology and drug discovery.

Computational conformational sampling underpins much of molecular modeling and design in pharmaceutical work. The sampling of smaller drug-like compounds has been an active area of research. However, few studies have tested in details the sampling of larger more flexible compounds, which are also relevant to drug discovery, including therapeutic peptides, macrocycles, and inhibitors of protein-protein interactions. Here, we investigate extensively mainstream conformational sampling methods on three carefully curated compound sets, namely the 'Drug-like', larger 'Flexible', and 'Macrocycle' compounds. These test molecules are chemically diverse with reliable X-ray protein-bound bioactive structures. The compared sampling methods include Stochastic Search and the recent LowModeMD from MOE, all the low-mode based approaches from MacroModel, and MD/LLMOD recently developed for macrocycles. In addition to default settings, key parameters of the sampling protocols were explored. The performance of the computational protocols was assessed via (i) the reproduction of the X-ray bioactive structures, (ii) the size, coverage and diversity of the output conformational ensembles, (iii) the compactness/extendedness of the conformers, and (iv) the ability to locate the global energy minimum. The influence of the stochastic nature of the searches on the results was also examined. Much better results were obtained by adopting search parameters enhanced over the default settings, while maintaining computational tractability. In MOE, the recent LowModeMD emerged as the method of choice. Mixed torsional/low-mode from MacroModel performed as well as LowModeMD, and MD/LLMOD performed well for macrocycles. The low-mode based approaches yielded very encouraging results with the flexible and macrocycle sets. Thus, one can productively tackle the computational conformational search of larger flexible compounds for drug discovery, including macrocycles.

A combined in vitro-in silico approach for the discovery of novel endogenous enzymatic and ctDNA sequence of bioactive molecules from aerial and root parts of Centaurea sulphurea as antioxidant's agents.

The excess free radicals not neutralized by the antioxidant defenses damage the essential macromolecules of our cells, causing abnormalities in the expression of genes and membrane receptors, cell proliferation or death, immune disorders, mutagenesis, deposits of proteins or lipofuschin in tissues. The first objective of this study was to elucidate the composition of the essential oil of the aerial and root part of Centaurea sulphurea during beginning of the vegetative cycle (March), beginning of the flowering stage (April) and full bloom (May/June) using GC/FID and GC/MS. The second aim was to describe the antioxidant activity using three methods (2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric-reducing antioxidant power (FRAP), ß-carotene bleaching assay) and bioinformatical study of ctDNA sequence and three endogenous enzymes inhibition. The essential oils obtained from the root during the full bloom period consisted mainly of caryophyllene oxide, aplotaxene and (Z)-phytol. While, the aerial parts were dominated by caryophyllene oxide, verridiflorol and humulene epoxide II. The results showed that essential oil presented an excellent antioxidant activity with IC50 values of 2.06 g/L and 1.29 g/L, for aerial and root parts, compared to butylated hydroxyltoluene (BHT) and Ethylenediaminetetraacetic acid (EDTA) controls and the nicotinamide adenine dinucleotide phosphate (NADPH) co-crystallized inhibitor. The results of the molecular docking revealed that (Z)-phytol (Ligand 39) has an affinity to interact with ctDNA sequence, and three targets Endogenous enzymes. The molecular dynamics study was conducted for the best inhibitors (Z)-phytol. A few key residues were identified at the binding site of receptors. The in-silico assessment of the ADME properties and BOILED-Egg plot reveals that compound (Z)-phytol (L39) is permeable to the blood brain barrier and have high lipophilicity and high coefficient of skin permeability in the intestines with good bioavailability. The ADMET analysis also showed that this oxygenated diterpene is safer to replace the synthetic drugs with side effects. Further testing is needed to assess its effectiveness in reducing oxidative stress for use in the pharmaceutical industry.Communicated by Ramaswamy H. Sarma.

Chemical composition variability and vascular endothelial growth factor receptors inhibitory activity of Inulaviscosa essential oils from Algeria.

Angiogenes is therefore appears to be a complex phenomenon, finely regulated by various activators (pro-angiogenic factors) and inhibitors (anti-angiogenic factors). Among the pro-angiogenic factors, VEGF (Vascular Endothelial Growth Factor) seems to be one of the main players in tumor angiogenesis. It exerts its pro-angiogenic activity by attaching to the surface of receptors with tyrosine kinase activity (VEGFR). The aim of this research was the bioinformatical study of VEGFR inhibition by essential oils of the Inula viscosa.Analyses of essential oils obtained by hydrodistillation from the aerial parts of the plant were performed using GC and GC/MS analysis. We used molecular modeling approaches as molecular mechanics to theoretical investigation VEGF receptors by natural inhibitors.Nineteen compounds were identified, constituting 90.1-98.8% of the total essential oils. The main components of the plants were (E)-nerolidol (15.5-20.2 %), caryophyllene oxide (10.6-18.1%), (E)-Z-farnesyl acetone (13.2-25.1%) and (E)-ß-farnesene (1.5-5.6%). Essential oil samples were clustered into two groups according to their chemical compositions. The molecular dynamics study was conducted for the best inhibitors. A few key residues were identified at the binding site of VEGFR. The Pharmacokinetics was justified by means of lipophilicity and high coefficient of skin permeability. The in silico evaluation of ADME revealed that L19 has high absorption. The essential oil of I. viscosa presents a significant variability. This study revealed that (E)-Z-Farnesylacetone is a functional inhibitor of VEGF activities and subsequently can be the best inhibitors candidate to be scrutinized in vivo and in vitro.Communicated by Ramaswamy H. Sarma.

Chemical composition/pharmacophore modelling- based, virtual screening, molecular docking and dynamic simulation studies for the discovery of novel superoxide dismutase (SODs) of bioactive molecules from aerial parts of Inula Montana as antioxydant's agents.

The accumulation of free radicals in the body develops chronic and degenerative diseases such as cancer, autoimmune diseases, rheumatoid arthritis, cardiovascular and neurodegenerative diseases. The first aim of this work was to study the chemical composition of Inula Montana essential oil using GC-FID and GC/MS analysis and the antioxidant activities using radical scavenging (DPPH) and the Ferric -Reducing Antioxidant Power (FRAP) tests. The second aim was to describe the assess the antioxidant activity and computational study of Superoxide Dismutase (SODs) and ctDNA inhibition. Sixty-nine compounds were identified in the essential oil of the aerial part of Inula montana. Shyobunol and α-Cadinol were the major compounds in the essential oil. The antioxidant power of the essential oil showed an important antioxidant effect compared to ascorbic acid and the methionine co-crystallized inhibitor. The results of the docking simulation revealed that E, E-Farnesyl acetate has an affinity to interact with binding models and the antioxidant activities of the ctDNA sequence and Superoxide Dismutase target. The penetration through the Blood-Brain Barrier came out to be best for E, E-Farnesyl acetate and E-Nerolidolacetate and was significantly higher than the control molecule and Lref. Finally, the application of ADMET filters gives us positive information on the compound E, E-Farnesyl acetate, which appears as a new inhibitor potentially more active towards ctDNA and SODs target. The active compounds, E,E-Farnesyl acetate can be used as templates for further development of more potent antioxidative agents.Communicated by Ramaswamy H. Sarma.

Statistical analysis/theoretical investigations of novel vascular endothelial growth factor of Davanoide from Scolymus grandifloras Desf as potent anti-angiogenic drug properties.

Many pro-angiogenic factors acting directly or indirectly on the proliferation and differentiation of endothelial cells have been highlighted, in particular: VEGF ('Vascular Endothelial Growth Factor'), FGF ('Fibroblast Growth Factor'), PDGF ('Platelet-Derived Growth Factor'), VEGF exerts its pro-angiogenic activity by binding to the surface of receptors with tyrosine kinase activity (VEGFR). The first objective of this study was to elucidate the composition of the essential oil of the roots of Scolymus grandifloras Desf. The second aim was to describe the intra-species variation in essential oil composition in natural populations of 21 oil samples from different Algerian locations using statistical analysis and bioinformatical study of VEGFR inhibition. The essential oil isolated from the root parts, was a really source of Davanoide compounds. The results of the docking simulation revealed that davanone (Ligand 13) has an affinity to interact with cDNA, VEGF and its receptors. The ADMET properties and BOILED-Egg plot validate the compound 13 pass the brain barrier and have high absorption in the intestines with good bioavailability. The findings of this study contribute to the pharmacological knowledge and the therapeutic efficacy of davanone and can initiate the development of new anti-angiogenic drugs. Results showed that essential oil of Scolymus grandiflorus presented a large level of percentage of davanone, davanol D1 and 2-hydroxy davanone. These components may be a new source of nontoxic anticancer agents. However, an additional in vitro and/or in vivo experimental study should make it possible to verify the theoretical results obtained in silico.Communicated by Ramaswamy H. Sarma.

Scaffold fragmentation and substructure hopping reveal potential, robustness, and limits of computer-aided pattern analysis (C@PA).

Computer-aided pattern analysis (C@PA) was recently presented as a powerful tool to predict multitarget ABC transporter inhibitors. The backbone of this computational methodology was the statistical analysis of frequently occurring molecular features amongst a fixed set of reported small-molecules that had been evaluated toward ABCB1, ABCC1, and ABCG2. As a result, negative and positive patterns were elucidated, and secondary positive substructures could be suggested that complemented the multitarget fingerprints. Elevating C@PA to a non-statistical and exploratory level, the concluded secondary positive patterns were extended with potential positive substructures to improve C@PA's prediction capabilities and to explore its robustness. A small-set compound library of known ABCC1 inhibitors with a known hit rate for triple ABCB1, ABCC1, and ABCG2 inhibition was taken to virtually screen for the extended positive patterns. In total, 846 potential broad-spectrum ABCB1, ABCC1, and ABCG2 inhibitors resulted, from which 10 have been purchased and biologically evaluated. Our approach revealed 4 novel multitarget ABCB1, ABCC1, and ABCG2 inhibitors with a biological hit rate of 40%, but with a slightly lower inhibitory power than derived from the original C@PA. This is the very first report about discovering novel broad-spectrum inhibitors against the most prominent ABC transporters by improving C@PA.

Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics.

The adenosine-triphosphate-(ATP)-binding cassette (ABC) transporter ABCA7 is a genetic risk factor for Alzheimer's disease (AD). Defective ABCA7 promotes AD development and/or progression. Unfortunately, ABCA7 belongs to the group of 'under-studied' ABC transporters that cannot be addressed by small-molecules. However, such small-molecules would allow for the exploration of ABCA7 as pharmacological target for the development of new AD diagnostics and therapeutics. Pan-ABC transporter modulators inherit the potential to explore under-studied ABC transporters as novel pharmacological targets by potentially binding to the proposed 'multitarget binding site'. Using the recently reported cryogenic-electron microscopy (cryo-EM) structures of ABCA1 and ABCA4, a homology model of ABCA7 has been generated. A set of novel, diverse, and potent pan-ABC transporter inhibitors has been docked to this ABCA7 homology model for the discovery of the multitarget binding site. Subsequently, application of pharmacophore modelling identified the essential pharmacophore features of these compounds that may support the rational drug design of innovative diagnostics and therapeutics against AD.

Functional metabolomics reveal the role of AHR/GPR35 mediated kynurenic acid gradient sensing in chemotherapy-induced intestinal damage.

Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan (Trp)-kynurenine (KYN)-kynurenic acid (KA) axis metabolism. Mechanistically, chemotherapy-induced intestinal damage triggered the formation of an interleukin-6 (IL-6)-indoleamine 2,3-dioxygenase 1 (IDO1)-aryl hydrocarbon receptor (AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35 (GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic. This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage.

Impact of virus-antibody interactions on viral clearance in anion exchange chromatography.

Viral clearance is an important performance metric for the downstream process of monoclonal antibodies (mAbs) due to its impact on patient safety. Anion exchange chromatography (AEX) has been well-accepted in the industry as one of the workhorse techniques for removing viruses, and is considered to be able to achieve high log clearance values under most operating conditions. However, it is not uncommon for viral clearance results on AEX to fall below the desired level despite operating under conditions that should achieve high clearance levels according to conventional wisdom of how this mode of chromatography operates. In this study, a design of experiment (DoE) approach was used to develop a more fundamental understanding of viral clearance during AEX chromatography using Minute Virus of Mice (MVM) on POROS HQ resin. Load pH, conductivity and virus concentration were evaluated as design factors for three mAbs with varying physical and chemical properties. The hydrophobicity and surface charge distributions of the molecules were found to be the most significant factors in influencing viral clearance performance, and the viral clearance trends did not seem to fit with conventional wisdom. To explain this seemingly unconventional behavior, we propose a new mechanism that suggests that interactions between the mAb and the virus have a major contribution on retention of the virus on the resin. This furthered understanding may help improve the predictability, performance and robustness of viral clearance during AEX chromatography.