Browsing by Author "Shadrack, Daniel M"

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    Hydrophobic π-π stacking interactions and hydrogen bonds drive self-aggregation of luteolin in water
    (Elsevier, 2022-06-23) Deogratias, Geradius; Shadrack, Daniel M; Munissi, Joan J.E.; Kinunda, Grace A.; Jacob, Fortunatus R.; Mtei, Regina P.; Masalu, Rose J.; Mwakyula, Issakwisa; Kiruri, Lucy W.; Nyandoro, Stephen S.
    Luteolin is a flavonoid obtained from different plant species. It is known for its versatile biological activities. However, the beneficial effects of luteolin have been limited to small concentrations as a result of poor water solubility. This study aimed at investigating the hydrophobic interaction and hydration of luteolin towards the improvement of its solubility when used as a drug. We report the aggregation properties of luteolin in water by varying the number of monomers using atomistic molecular dynamics simulation. Results show that the equilibrium structure of luteolin occurs in an aggregated state with different structural arrangements. As the monomers size increase, the antiparallel flipped conformation dominates over T-shaped antiparallel, T-shaped parallel, and antiparallel conformations. The formation of intramolecular hydrogen bonding of 0.19 nm between the keto-enol groups results in hydrophobic characteristics. A larger cluster exhibits slow hydrogen bond dynamics for luteolin-luteolin than luteolin-water interaction. Water structure at large cluster size exhibited slow dynamics and low self-diffusion of luteolin. The existence of hydrophobic π-π and hydrogen bonds between luteolin molecules drives strong self-aggregation resulting in poor water solubility. Breakage of these established interactions would result in increased solubility of luteolin in water.
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    In silico pharmacokinetic, molecular docking and molecular dynamics simulation studies of n-cinnamoyltetraketide derivatives as inhibitors of cyclooxygenase-2 enzyme
    (Dar es Salaam University Press, 2018-06) Nyandoro, Stephen S.; Shadrack, Daniel M; Munissi, Joan J.E; Mubofu, Egid B.
    Recent phytochemical analysis of Toussaintia orientalis leaves yielded series of novel bioactive N-cinnamoyltetraketide derivatives namely toussaintines A-G (t_1 - t_8) some portraying cytotoxicity against the triple negative aggressive human breast cancer cell line (MDA-MB-231) among other potencies. Despite having broad bioactivity spectrum, their general drug-likeness profiles and mode of action (simulated or actual) targeting any enzyme remains uninvestigated. In silico pharmacokinetic, drug-likeness descriptors and molecular docking of the compounds t_1-t_8 targeting inhibition of cyclooxygenase-2 (COX-2) enzyme were evaluated. The Lipinski Rule of Five heralded the pharmacokinetic properties of the studied metabolites. The studied compounds were docked with COX-2 following already established protocol. ADMET descriptors fell within the recommended range, except for compound t_3 that was predicted to potentially have positive blood brain barrier (BBB+) penetration. Docking studies indicated N-cinnamoyltetraketide derivatives as potential inhibitors of COX-2 enzyme. Compounds t_3 and t_5 showed lower binding energy of -13 and -12.3 kcal/mol, respectively, being closely comparable to celecoxib (-12.3 kcal/mol) indicating compatibility with the protein receptor. The findings provide baseline information on drug or lead-likeness and potential mode of action of the studied molecules towards inhibition of COX-2 enzyme
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    Polyamido(amine) Dendrimers for Enhanced Solubility of Small Molecules and Other Desirable Properties for Site Specific Delivery: Insights from Experimental and Computational Studies
    (MDPI, 2018-06-12) Shadrack, Daniel M; Swai, Hulda S.; Munissi, Joan J.E; Mubofu, Egid B.; Nyandoro, Stephen S.
    Clinical applications of many small molecules are limited due to poor solubility and lack of controlled release besides lack of other desirable properties. Experimental and computational studies have reported on the therapeutic potential of polyamidoamine (PAMAM) dendrimers as solubility enhancers in pre-clinical and clinical settings. Besides formulation strategies, factors such as pH, PAMAM dendrimer generation, PAMAM dendrimer concentration, nature of the PAMAM core, special ligand and surface modifications of PAMAM dendrimer have an influence on drug solubility and other recommendable pharmacological properties. This review, therefore, compiles the recently reported applications of PAMAM dendrimers in pre-clinical and clinical uses as enhancers of solubility and other desirable properties such as sustained and controlled release, bioavailability, bio-distribution, toxicity reduction or enhancement, and targeted delivery of small molecules with emphasis on cancer treatment.