The analysis of the essential oil from rhizome and roots of Ferula hermonis Boiss. (Apiaceae) by GC–FID, GC–MS and 13C NMR allowed the identification of 79 constituents, more than 90% of the oil, the major one being a-pinene (43.3%), followed by a-bisabolol (11.1%) and the unusual acetylenic compound 3,5-nonadiyne (4.4%). The antifungal activity of the essential oil before and after fractionation was assayed against several yeasts and filamentous fungi. Purification of the active fractions afforded 3,5-nonadiyne, a-bisabolol, jaeschkeanadiol angelate, a-bisabolol oxide B and trans-verbenol, as well as two purified fractions, one of them (JB73) with 73% of jaeschkeanadiol benzoate and the other with 50% of spathulenol. Determination of MIC and MFC values of all these products evidenced strong antifungal activities for JB73 and 3,5-nonadiyne. Particularly, against the dermatophyte Tricophyton mentagrophytes, MIC and MFC values were 0.25 lg/ml for JB73, and 8 lg/ml for 3,5-nonadiyne, the former being more active than amphotericin B and nystatin.

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Journal: Phytochemistry 72 1406-1413

The antifungal activity of hexane, dichloromethane, methanol and aqueous extracts from the rhizome and root of Ferula hermonis was assayed in vitro by the agar disk diffusion method against a panel of human opportunistic and pathogenic fungi. Among them, the hexane and dichloromethane extracts showed the highest activity particularly against the dermatophytes Microsporum gypseum and Tricophyton mentagrophytes as well as the yeast Candida lactis-condensi. Activity-guided fractionation of both extracts using an agar overlay bioautographic method led to the isolation of two antifungal compounds which were identified as the daucane aryl esters jaeschkeanadiol p-hydroxybenzoate (ferutinin) and jaeschkeanadiol benzoate (teferidin). Determination of minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values of both compounds evidenced a stronger antifungal activity for ferutinin than for teferidin. Particularly, T. mentagrophytes was the most sensitive strain with MIC and MFC values ranging from 8 to 256 mg/mL.

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Journal: Phytotherapy Research, 27: 911-915

In this study fragment-based drug design is combined with molecular docking simulation technique, to design databases of virtual sialic acid (SA) analogues with new substitutions at C2, C5 and C6 positions of SA scaffold. Using spaces occupied by C2, C5 and C6 natural moieties of SA when bound to hemagglutinin (HA) crystallographic structure, new fragments that are commercially available were docked independently in all the pockets. The oriented fragments were then connected to the SA scaffold with or without incorporation of linker molecules. The completed analogues were docked to the whole SA binding site to estimate their binding conformations and affinities, generating three databases of HA-bound SA analogues. Selected new analogues showed higher estimated affinities than the natural SA when tested against H3N2, H5N1 and H1N1 subtypes of influenza A. An improvement in the binding energies indicates that fragment-based drug design when combined with molecular docking simulation is capable to produce virtual analogues that can become lead compound candidates for anti-flu drug discovery program.

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Journal: J Mol Model. 2010 May;16(5):975-91

A molecular docking tool of AutoDock3.05 was evaluated for its ability to reproduce experimentally determined affinities of various sialic acid analogues toward hemagglutinin of influenza A virus. With the exception of those with a C6-modified glycerol side chain, the experimental binding affinities of most sialic acid analogues (C2, C4 and C5-substituted) determined by viral hemadsorption inhibition assay, hemagglutination inhibition assay and nuclear magnetic resonance correlated well with the computationally estimated free energy of binding. Sialic acid analogues with modified glycerol side chains showed only poor correlation between the experimentally determined hemagglutinin inhibitor affinities and AutoDock3.05 scores, suggesting high mobility of the glutamic acid side chain at the glycerol binding pocket, which is difficult to simulate using a flexi-rigid molecular docking approach. In conclusion, except for some glycerol-substituted sialic acid analogues, the results showed the effectiveness of AutoDock3.05 searching and scoring functions in estimating affinities of sialic acid analogues toward influenza A hemagglutinin, making it a reliable tool for screening a database of virtually designed sialic acid analogues for hemagglutinin inhibitors.

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Journal: J Mol Model. 2010 May;16(5):1047-58.

BACKGROUND: Glutathione-s-transferases (GSTs) are enzymes that principally catalyze the conjugation of electrophilic compounds to the endogenous nucleophilic glutathione substrate, besides, they have other non-catalytic functions. The Plasmodium falciparum genome encodes a single isoform of GST (PfGST) which is involved in buffering the toxic heme, thus considered a potential anti-malarial target. In mammals several classes of GSTs are available, each of various isoforms. The human (human GST Pi-1 or hGSTP1) and mouse (murine GST Mu-1 or mGSTM1) GST isoforms control cellular apoptosis by interaction with signaling proteins, thus considered as potential anti-cancer targets. In the course of GSTs inhibitors development, the models of ligands interactions with GSTs are used to guide rational molecular modification. In the absence of X-ray crystallographic data, enzyme kinetics and molecular docking experiments can aid in addressing ligands binding modes to the enzymes. METHODS: Kinetic studies were used to investigate the interactions between the three GSTs and each of glutathione, 1-chloro-2,4-dinitrobenzene, cibacron blue, ethacrynic acid, S-hexyl glutathione, hemin and protoporphyrin IX. Since hemin displacement is intended for PfGST inhibitors, the interactions between hemin and other ligands at PfGST binding sites were studied kinetically. Computationally determined binding modes and energies were interlinked with the kinetic results to resolve enzymes-ligands interaction models at atomic level. RESULTS: The results showed that hemin and cibacron blue have different binding modes in the three GSTs. Hemin has two binding sites (A and B) with two binding modes at site-A depending on presence of GSH. None of the ligands were able to compete hemin binding to PfGST except ethacrynic acid. Besides bind differently in GSTs, the isolated anthraquinone moiety of cibacron blue is not maintaining sufficient interactions with GSTs to be used as a lead. Similarly, the ethacrynic acid uses water bridges to mediate interactions with GSTs and at least the conjugated form of EA is the true hemin inhibitor, thus EA may not be a suitable lead. CONCLUSIONS: Glutathione analogues with bulky substitution at thiol of cysteine moiety or at γ-amino group of γ-glutamine moiety may be the most suitable to provide GST inhibitors with hemin competition.

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Journal: Comput Biol Chem. 2016 Oct;64:237-249.

The carbon nanotube (CNT)-based target-specific delivery of drugs, or other molecular cargo, has emerged as one of the most promising biomedical applications of nanotechnology. To achieve efficient CNT-based drug delivery, the interactions between the drug, CNT and biomolecular target need to be properly optimized. Recent advances in the computer-aided molecular design tools, in particular molecular dynamics (MD) simulation studies, offer an appropriate low-cost approach for such optimization. This review highlights the various potential MD approaches for the simulation of CNT interactions with cell membranes while emphasizing various methods of cellular internalization and toxicities of CNTs to build new strategies for designing rational CNT-based targeted drug delivery to circumvent the limitations associated with the various clinically available nonspecific therapeutic agents

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Journal: Drug Discov Today. 2018 Feb;23(2):235-250

Modulating cellular processes through extracellular chemical stimuli is medicinally an attractive approach to control disease conditions. GPCRs are the most important group of transmembranal receptors that produce different patterns of activations using intracellular mediators (such as G-proteins and Beta-arrestins). Adenosine receptors (ARs) belong to GPCR class and are divided into A1AR, A2AAR, A2BAR and A3AR. ARs control different physiological activities thus considered valuable target to control neural, heart, inflammatory and other metabolic disorders. Targeting ARs using small molecules is essentially works through binding to orthosteric and/or allosteric sites of the receptors. Although targeting orthosteric site is considered typical to modulate receptor activity, allosteric sites provide better subtype selectivity, saturable modulation of activity and variable activation patterns. Each receptor exists in dynamical equilibrium between conformational ensembles, the equilibrium is affected by receptor interaction with other molecules. Changing the population of conformational ensembles of the receptor is the method by which orthosteric, allosteric and other cellular components controls receptor signaling. Herein, the interactions of ARs with orthosteric, allosteric ligands as well as intracellular mediators are described. A quinary interaction model for the receptor is proposed and energy wells for major conformational ensembles are retrieved

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Journal: Curr Pharm Des. 2019 Mar 4

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Journal: Journal of Pharmaceutical Health Services Research, Volume 9 Issue 4 Pages 373-379

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Journal: Clinical pharmacology: advances and applications, Volume 10 Pages 63

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Journal: Powder technology, Volume 214 Issue 1 Pages 161-168