Abstract Naproxen, as a propionic acid derivative, causes serious gastrointestinal side effects due to the presence of free carboxylic group. In that sense, masking of carboxylic group with other ...pharmacophores may be a promising strategy to decrease gastrointestinal toxicity. Thiourea derivatives have been intensively investigated as potential antitumor drugs, whereby their activity is based on potential inhibition of protein kinases, topoisomerases, carbonic anhydrase and sirtuins. In addition, it was shown that inhibition of certain protein kinases might reverse resistance to chemotherapeutic drugs by enhancing the cell death in the presence of low concentrations of drug. Twenty new thiourea derivatives of naproxen were designed and their binding to four selected protein kinases involved in tumor multidrug resistance (AKT2, mTOR, EGFR and VEGFR1) was estimated using two molecular docking programs (AutoDock Vina and OEDocking). According to OEDocking, the highest potential to inhibit AKT2 and mTor has derivative 1, while derivative 20 demonstrates the highest potential towards EGFR and VEGFR1. According to AutoDock Vina, the highest potential for inhibition of EGFR, AKT2 and VEGFR1 have derivatives 16 and 17. Therefore, derivatives 1, 16, 17 and 20 are potentially the most potent protein kinase inhibitors that could be further synthesized and tested for anticancer activity.
•A series of 8-benzimidazolyl-coumarin-3-oxadiazoles were synthesized. The chemistry involved is very interesting.•Synthesized coumarin derivatives exhibited very good to moderate Anti-proliferative ...potency.•Compounds 10b, 10c and 10g are the potent compounds out of 10 compounds synthesized with significant IC50 values of 9.26 μg/mL, 14.58 μg/mL and 12.89 μg/mL respectively.•The molecular docking study revealed lower binding energy with the target protein which is also very crucial parameter to serve as molecular templates for the effective treatment of breast cancer cells.
A series of 8-benzimidazolyl-coumarin-3-oxadiazoles (10a-j) were synthesized and evaluated their anti-cancer activity against breast cancer using MCF-7 cell lines. Out of 10 tricore hybrids synthesized, the compound 10b with 2,4-dimethyl phenyl substitution on the oxadiazole ring is emerged as most potent compound with the IC50 value of 9.26 μg/mL compared to the IC50 value of the standard drug doxorubicin 7.54 μg/mL. The compound 10g with 2,6-difluoro phenyl substituted, 10c with 3‑methoxy benzyl substituted and 10e with 4‑chloro phenyl substitution on the oxadiazole ring are the other analogues with significant anti-cancer activity. The molecular docking studies using Autodock Vina tool revealed that the tested ligands have lower binding energy with the receptor protein quinone reductase-2 (PDB ID - 4ZVM) than the standard drug doxorubicin and exhibited similar amino acid interactions.
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An rare pandemic of viral pneumonia occurs in December 2019 in Wuhan, China, which is now recognized internationally as Corona Virus Disease 2019 (COVID-19), the etiological agent classified as ...Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2). According to the World Health Organization (WHO), it has so far expanded to more than 213 countries/territories worldwide. Our study aims to find the viral peptides of SARS-COV-2 by peptide mass fingerprinting (PMF) in order to predict its novel structure and find an inhibitor for each viral peptide. For this reason, we calculated the mass of amino acid sequences translated from the SARS-CoV2 whole genome and identify the peptides that may be a target for inhibition. Molecular peptide docking with Moringa oleifera, phytochemicals (aqueous and ethanolic) leaf extracts of flavonoids (3.56 ± 0.03), (3.83 ± 0.02), anthraquinone (11.68 ± 0.04), (10.86 ± 0.06) and hydroxychloroquine present therapy of COVID-19 in Pakistan for comparative study. Results indicate that 15 peptides of SARS-CoV2 have been identified from PMF, which is then used as a selective inhibitor. The maximum energy obtained from AutoDock Vina for hydroxychloroquine is -5.1 kcal/mol, kaempferol (flavonoid) is -6.2 kcal/mol, and for anthraquinone -6 kcal/mol. Visualization of docking complex, important effects are observed regarding the binding of peptides to drug compounds. In conclusion, it is proposed that these compounds are effective antiviral agents against COVID-19 and can be used in clinical trials.
Communicated by Ramaswamy H. Sarma
'Malvazija istarska' (Vitis vinifera L.) jedna je od najznačajnijih bijelih sorata u Hrvatskoj. Njezina kvaliteta prepoznata je kako u Hrvatskoj, tako i u cijelom svijetu. Stoga se domaći proizvođači ...sve češće odlučuju za proizvodnju vina i pjenušaca iz ove sorte. Mošt za proizvodnju baznoga vina za pjenušce po svome sastavu trebao bi zadovoljavati svojstva kao što su niža pH vrijednost i sadržaj šećera, te viši sadržaj ukupne kiselosti s većim udjelom vinske kiseline, naspram jabučne. S obzirom da se 'Malvazija istarska' uzgaja pretežito u Istri, gdje je klima mediteranska, a najzastupljenije tlo crvenica teško je zadovoljiti sva navedena svojstva, posebice u suhim i vrućim godinama. Stoga, cilj ovog istraživanja bio je utvrditi mogućnost pozitivnog djelovanja folijarne gnojidbe na navedena svojstva. Pokus je postavljen na sorti Malvazija istarska na podlozi SO4 2013. s četiri gnojidbena tretmana (T1- NPK, T2 - NPK + Agromag 6L (6% MgO), T3 - NPK + Agromag 6L + Fosforo 30L (30% P2O5) i T4 - NPK + Agromag 6L + Fosforo 30L + Bio Prot) u tri ponavljanja po slučajnom bloknom rasporedu (RCBD). Sveukupno određena pH vrijednost u moštu kretala se od 3,02 do 3,29, ukupna kiselost u moštu od 7,80 do 9,03 g/L, a sadržaj šećera od 76,00 – 81,00 °Oe. Najveća utvrđena koncentracija vinska kiselina bila je 4,49 g/l u tretmanu T3, koji je imao i najnižu utvrđenu koncentraciju jabučne kiseline 1,40 g/L. Značajan pozitivan utjecaj na sva svojstva imao je tretman T4.
There is a growing interest in the mechanisms and the prediction of how flexible peptides bind proteins, often in a highly selective and conserved manner. While both existing small-molecule docking ...methods and custom protocols can be used, even short peptides make difficult targets owing to their high torsional flexibility. Any benchmarking should therefore start with those. We compiled a meta-data set of 47 complexes with peptides up to five residues, based on 11 related studies from the past decade. Although their highly varying strategies and constraints preclude direct, quantitative comparisons, we still provide a comprehensive overview of the reported results, using a simple yet stringent measure: the quality of the top-scoring peptide pose. Using the entire data set, this is augmented by our own benchmark of AutoDock Vina, a freely available, fast and widely used docking tool. It particularly addresses non-expert users and was therefore implemented in a highly integrated manner. Guidelines addressing important issues such as the amount of sampling required for result reproducibility are so far lacking. Using peptide docking as an example, this is the first study to address these issues in detail. Finally, to encourage further, standardized benchmarking efforts, the compiled data set is made available in an accessible, transparent and extendable manner.
The accuracy of five docking programs at reproducing crystallographic structures of complexes of 8 macrolides and 12 related macrocyclic structures, all with their corresponding receptors, was ...evaluated. Self-docking calculations indicated excellent performance in all cases (mean RMSD values ≤ 1.0) and confirmed the speed of AutoDock Vina. Afterwards, the lowest-energy conformer of each molecule and all the conformers lying 0-10 kcal/mol above it (as given by Macrocycle, from MacroModel 10.0) were subjected to standard docking calculations. While each docking method has its own merits, the observed speed of the programs was as follows: Glide 6.6 > AutoDock Vina 1.1.2 > DOCK 6.5 >> AutoDock 4.2.6 > AutoDock 3.0.5. For most of the complexes, the five methods predicted quite correct poses of ligands at the binding sites, but the lower RMSD values for the poses of highest affinity were in the order: Glide 6.6 ≈ AutoDock Vina ≈ DOCK 6.5 > AutoDock 4.2.6 >> AutoDock 3.0.5. By choosing the poses closest to the crystal structure the order was: AutoDock Vina > Glide 6.6 ≈ DOCK 6.5 ≥ AutoDock 4.2.6 >> AutoDock 3.0.5. Re-scoring (AutoDock 4.2.6//AutoDock Vina, Amber Score and MM-GBSA) improved the agreement between the calculated and experimental data. For all intents and purposes, these three methods are equally reliable.
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•Chemical composition and functional activities of known essential oils.•Xanthine Oxidase bovine milk is more advantageous enzyme source in terms results, and savings.•Double enzyme ...detection is an innovative method approved its efficacy and quickness.
In pharmaceutical labs, the major sources of xanthine oxidase enzyme (XO) used for the gout disease experiment are animals and humans. The aim of this study is to find the lucrative source for the experiment by the evaluation in vitro and in silico of the inhibitory activity of five essential oils (EOs), against human and bovine milk xanthine oxidase (HXO and BXO), using molecular docking and an innovative analysis method based on double enzyme detection (DED), investigated in this work for the first time. The DED method proved its efficacy, sensitivity, and quickness. The results show that the five EOs give an important inhibition to BXO and HXO with an IC50 of 3.67 ± 0.17 μg/ml, 3.89 ± 0.11 μg/ml, 3.76 ± 0.18 μg/ml, 2.37 ± 0.23 μg/ml, 3.43 ± 0.56 μg/ml for HXO, and to BXO with an IC50 of 6.26 ± 0.92 μg/ml, 5.53 ± 0.82 μg/ml, 10.59 ± 1.59 μg/ml, 1.74 ± 1 μg/ml, 5.33 ± 0.13 μg/ml, for respectively, cumin (Cuminum cyminum L.), fennel (Foeniculum vulgare Mill.), coriander (Coriandrum sativum L.), anise (Pimpinella anisum L.), and caraway (Carum carvi L.) EOs. In silico study based on molecular docking using autodock vina program was carried out to study the BXO and HXO inhibition mechanism and involved interactions for the first time. The results show that the five used EOs give an important and similar inhibition effect against XO with both enzyme sources, therefore we propose the bovine milk as a new economic enzyme source for lab experiment, which can promote a new, approach in future gout treatment.
The protostome leucokinin (LK) signaling system, including LK peptides and their G protein-coupled receptors, has been characterized in several species. Despite the progress, molecular mechanisms ...governing LK peptide–receptor interactions remain to be elucidated. Previously, we identified a precursor protein for Aplysia leucokinin-like peptides (ALKs) that contains the greatest number of amidated peptides among LK precursors in all species identified so far. Here, we identified the first ALK receptor from Aplysia, ALKR. We used cell-based IP1 activation assays to demonstrate that two ALK peptides with the most copies, ALK1 and ALK2, activated ALKR with high potencies. Other endogenous ALK-derived peptides bearing the FXXWX-amide motif also activated ALKR to various degrees. Our examination of cross-species activity of ALKs with the Anopheles LK receptor was consistent with a critical role for the FXXWX-amide motif in receptor activity. Furthermore, we showed, through alanine substitution of ALK1, the highly conserved phenylalanine (F), tryptophan (W), and C-terminal amidation were each essential for receptor activation. Finally, we used an artificial intelligence–based protein structure prediction server (Robetta) and Autodock Vina to predict the ligand-bound conformation of ALKR. Our model predicted several interactions (i.e., hydrophobic interactions, hydrogen bonds, and amide-pi stacking) between ALK peptides and ALKR, and several of our substitution and mutagenesis experiments were consistent with the predicted model. In conclusion, our results provide important information defining possible interactions between ALK peptides and their receptors. The workflow utilized here may be useful for studying other ligand–receptor interactions for a neuropeptide signaling system, particularly in protostomes.
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