Browsing by Author "Shadrack, Daniel M."

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A computational study on the role of water and conformational fluctuations in Hsp90 in response to inhibitors
(Elsevier Inc., 2020-05) Shadrack, Daniel M.; Swai, Hulda; Hassanali, Ali
Molecular chaperone Heat Shock Protein 90 (Hsp90) represents an interesting chemotherapeutic target for cancer treatments as it plays a role in cancer proliferation. Thus, continued effort to identify novel inhibitors of this target is an important task. Drug design using computational approach has gained significant attention in recent years. This work aims to propose docking protocols to re-purpose FDA-approved drugs targeting Hsp90. Sensitivity of results to different docking protocols such apo, holo and receptor ensembles (relaxed complex) structures, the role of water and conformational changes of Hsp90, are described. We show that the protein conformation and water have effects on drug binding. Holo relaxed complex receptors ensembles improves the binding energy of ligands to the protein. We also compare and contrast structural stability of three drugs namely: ezetimibe, pitavastatin and vilazodon in the Hsp90 protein. The results obtained serves as a possible basis towards developing Hsp90 inhibitors.
Polyamidoamine 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; 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.
Solvent effects on host-guest residence time and kinetics: further insights from metadynamics simulation of Toussaintine-A unbiding from chitosan nanoparticle
(Springer Nature Switzerland AG., 2021-04-14) Shadrack, Daniel M.; Kiruri, Lucy W.; Swai, Hulda; Nyandoro, Stephen S.
Solvents play an important role in host-guest intermolecular interactions. The kinetics and residence time of Toussaintine-A (TouA) unbinding from chitosan was investigated by means of well-tempered metadynamics and thermodynamic integration using two solvents, polar aprotic (DMSO), and polar protic (water). The kinetic rates were found to be strongly dependent on the solvent polarity; hence, the unbinding rate proceeded much faster in DMSO compared to water. DMSO tends to participate less in a chemical reaction by weakening the intermolecular interaction between chitosan and TouA due to lack of acidic hydrogen resulting in a reduction of the transition state. On the other hand, water, which ought to donate hydrogen atoms, sustains a strong interaction and hence large barrier heights. Consequently, this reduces the unbinding rate and increases the residence time. Binding free energy from thermodynamic integration suggests a thermodynamic stable chitosan-TouA complex in water than in DMSO.
Solvent effects on molecular encapsulation of Toussantine-A by chitosan nanoparticle: A metadynamics study
(Elsevier, 2019-10-15) Shadrack, Daniel M.; Swai, Hulda
We report a metadynamics study of toussantine-A with chitosan nanoparticle in dimethyl sulfoxide and water in order to assess the solvent related effects on free energy and interaction stability between the two compounds. We use well-tempered metadynamics to characterize the binding and unbinding processes of toussantine-A from chitosan. The calculated binding free energies support unbinding process deduced from metadynamics simulation. Toussantine-A interacts poorly with chitosan in the presence of dimethyl sulfoxide when compared to water; the dimethyl sulfoxide gives rising a reverse effect on drug binding that favours to the unbinding of toussantine-A.