研究领域
Design and Structural Investigation of Dendrimers
Dendrimers, well-defined branched symmetrical macromolecules, used for targeted drug delivery by encapsulation or conjugation of drugs on the surface. Molecular dynamics simulations are used to understand their structure, physicochemical properties and intermolecular interactions. We are using this information to computationally design macromolecular dendrimer based with optimal properties useful for treating diseases (Barata et al, Biomaterials, doi:10.1016/j.biomaterials.2011.07.085),
The molecular modeling of hyperbranched molecules is currently constrained by difficulties in model building, due partly to lack of parameterization of their building blocks and branched topology. We have addressed this problem by developing a method that translates monomeric linear sequences into a full atomistic model of a hyperbranched molecule (Barata et al, J. Mol. Mod. DOI: 10.1007/s00894-011-0966-y). Such molecular-modeling-based advances are enabling theoretical studies of important biological interactions between naturally occurring macromolecules and synthetic macromolecules (Barata et al, PLOS Comp. Biol. doi:10.1371/journal.pcbi.1002095). Our results also suggest that it should be possible to apply this sequence-based methodology to generate hyperbranched structures of other dendrimeric structures and of linear polymers.
In silico Screening for Modulators of Efflux Pumps
The ineffectiveness of antibiotics and anticancer drugs can be caused by multidrug resistance (MDR). The activity of drugs can be restored by co-administration of efflux pump modulators. We have proposed that modulators of MDR might form complexes with substrates of efflux pumps to act as “escort” molecules and deliver drugs to the site of action (Zloh et al., Bioog. Med. Chem Lett. doi:10.1016/j.bmcl.2003.12.015). We have evaluated interaction energies between a series of drugs and MDR modulators and confirm a qualitative correlation with potentiating ability of “escort” molecules. Additionally, the change of log P of complexes might be responsible for overcoming the membrane impermeability and the activity of drugs in the presence of the modulators. This suggests that interactions between small molecules may play an important role in overcoming biological barriers in bacteria.
Furthermore we have demonstrated that GRID and GLUE (www.moldiscovery.com) can be used in a qualitative way to predict complex formation between two small molecules, and as such it has the potential to be used for in silico screening of modulators of efflux pumps. A combination of similarity search and assessment of interaction energies and physicochemical properties of complexes formed between norfloxacin and potential escort molecules was utilized to search for “escort” molecules. Two already FDA approved drugs from the SuperDrug database were found to potentiate the activity of norfloxacin against multidrug-resistant S. aureus. This study could be expanded by querying other databases of molecules, and it has the potential to be utilized for the discovery of “escort” molecules for other drugs that are effluxed by multidrug-resistant cells.
Molecular Modelling and Dynamics of PEGylated Proteins
PEGylation is a clinically proven strategy for increasing the therapeutic efficacy of protein-based medicines. Site-specific PEGylation methodology developed by PolyTherics exploits the thiol selective chemistry of the two cysteine sulfur atoms from an accessible disulfide. It involves two key steps: (1) disulfide reduction to release the two cystine thiols, and (2) bis-alkylation to give a three-carbon bridge to which PEG is covalently attached. We are using molecular dynamics simulation to demonstrate that irreversible denaturation of the protein does not occur during this process (Zloh et al., Nature Protocols, doi: 10.1038/nprot.2007.119). Our computational studies have supported experiments and shown that peptides, proteins, enzymes and antibody fragments can be site-specifically PEGylated using a native and accessible disulfide without destroying the molecules' tertiary structure or abolishing its biological activity. These studies are being expanded on understanding of other approaches to PEGylation of proteins.
Spectral Database Design and Chemometrics
The influx of medicines from different sources into healthcare systems of developing countries presents a challenge to monitor their origin and quality. The absence of a repository of reference samples or spectra prevents the analysis of tablets by direct comparison. A spectral database of pharmaceutical and herbal formulations was created and search methods were evaluated for correct identification of tablets (Said et al, doi:10.1016/j.ijpharm.2011.05.057). This approach is being further developed as a method for identifying substandard pharmaceutical products on the market or dispensed to patients.
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Identification of excipient-protein interaction hotspots using computational approachesBarata, T. S., Zhang, C., A. Darby, P., Brocchini, S. & Zloh, M. 1 Jun 2016 In : International Journal of Molecular Sciences. 17, 6, p. 853 20 p., 853
Evidence that Diclofenac and Celecoxib are thyroid hormone receptor beta antagonistsZloh, M., Perez Diaz, N., Tang, L., Patel, P. & MacKenzie, L. S. 1 Feb 2016 In : Life sciences. 146, p. 66-72
Application of diffusion-edited and solvent suppression 1H NMR to the direct analysis of markers in valerian-hop liquid herbal productsPrieto, J. M., Mellinas-Gomez, M. & Zloh, M. 2016 In : Phytochemical Analysis. 27, 2, p. 100-106 7 p.
Small molecule recognition of mephedrone using an anthracene molecular clipKellett, K., Broome, J. H., Zloh, M., Kirton, S. B., Fergus, S., Gerhard, U., Stair, J. L. & Wallace, K. J. 2016 In : Chemical Communications. 52, 47, p. 7474-7477 4 p.
In silico modelling of prostacyclin and other lipid mediators to nuclear receptors reveal novel thyroid hormone beta receptor antagonist properties.Perez Diaz, N., Zloh, M., Patel, P. & MacKenzie, L. S. 11 Dec 2015 In : Prostaglandins and Other Lipid Mediators. 122, p. 18-27
Survey of knowledge of legal highs (novel psychoactive substances) amongst London pharmacistsGuirguis, A., Corkery, J., Stair, J., Kirton, S., Zloh, M., Goodair, C., Schifano, F. & Davidson, C. Jun 2015 In : Drugs and Alcohol Today. 15, 2, p. 93-99
Antagonistic effects of indoloquinazoline alkaloids on antimycobacterial activity of evocarpineHochfellner, C., Evangelopoulos, D., Zloh, M., Wube, A., Guzman, J. D., Mchugh, T. D., Kunert, O., Bhakta, S. & Bucar, F. 1 Apr 2015 In : Journal of Applied Microbiology. 118, 4, p. 864-872 9 p.
Correction to "Production of water-soluble few-layer graphene mesosheets by dry milling with hydrophobic drug"
Rubio, N., Serra-Maia, R., Kafa, H., Mei, K-C., Pach, E., Luckhurst, W., Zloh, M., Festy, F., Richardson, J. P., Naglik, J. R., Ballesteros, B. & Al-Jamal, K. T. 24 Feb 2015 In : Langmuir : the ACS journal of surfaces and colloids. 31, 7, p. 2249
Intramolecular cyclization of β-nitroso-o-quinone methides: A theoretical endoscopy of a potentially useful innate 'reclusive' reactionTzeli, D., Tsoungas, P. G., Petsalakis, I. D., Kozielewicz, P. & Zloh, M. 14 Jan 2015 In : Tetrahedron. 71, 2, p. 359-369 11 p.
Synthesis and evaluation of antibacterial activity of series of novel diketonesRossiter, S., Zloh, M., Bassin, J., Singh, J. & Goyal, M. 2015
Production of water-soluble few-layer graphene mesosheets by dry milling with hydrophobic drugRubio, N., Serra-Maia, R., Kafa, H., Mei, K. C., Al-Jamal, K. T., Luckhurst, W., Zloh, M., Festy, F., Richardson, J. P., Naglik, J. R., Pach, E. & Ballesteros, B. 16 Dec 2014 In : Langmuir. 30, 49, p. 14999-15008 10 p.
Molecular modeling to study dendrimers for biomedical applicationsMartinho, N., Florindo, H., Silva, L., Brocchini, S., Zloh, M. & Barata, T. 8 Dec 2014 In : Molecules. 19, 12, p. 20424-20467 44 p.
Arene-fused 1,2-oxazole N-oxides and derivatives. The impact of the N-O dipole and substitution on their aromatic character and reactivity profile. Can it be a useful structure in synthesis? A theoretical insightKozielewicz, P., Tzeli, D., Tsoungas, P. G. & Zloh, M. 1 Dec 2014 In : Structural Chemistry. 25, 6, p. 1837-46
Computational classification models for predicting the interaction of drugs with P-glycoprotein and breast cancer resistance proteinErić, S., Kalinić, M., Ilić, K. & Zloh, M. Dec 2014 In : SAR and QSAR in Environmental Research. 25, 12, p. 939-966 28 p.
β-Nitroso-o-Quinone Methides: Potent Intermediates in Organic Chemistry and Biology: The impact of the NO group on their Structure and Reactivity Profile: a Theoretical InsightKozielewicz, P., Tsoungas, P., Zloh, M., Tzeli, D. & Petsalakis, I. Dec 2014 In : Structural Chemistry. 25, 6, p. 1711-1723
Structural insights into binding of small molecule inhibitors to Enhancer of Zeste Homolog 2Kalinić, M., Zloh, M. & Erić, S. Nov 2014 In : Journal of Computer-Aided Molecular Design. 28, 11, p. 1109-1128
Rapid detection of sildenafil analogue in Eurycoma longifolia products using a new two-tier procedure of the near infrared (NIR) spectra databaseSaid, M. M., Gibbons, S., Moffat, A. C. & Zloh, M. 1 Sep 2014 In : Food Chemistry. 158, p. 296-301 6 p.
Bioadhesive tablets containing cyclodextrin complex of Itraconazole for the treatment of vaginal candidiasisCevher, E., Açma, A., Sinani, G., Aksu, B., Zloh, M. & Mülazımoğlu, L. Aug 2014 In : International Journal of Biological Macromolecules. 69, p. 124-136
Insights into mechanism of anticancer activity of pentacyclic oxindole alkaloids of Uncaria tomentosa by means of a computational reverse virtual screening and molecular docking approachKozielewicz, P., Paradowska, K., Eric, S., Wawer, I. & Zloh, M. 1 Jul 2014 In : Monatshefte für Chemie/Chemical Monthly. 145, 7, p. 1201-1211
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