Mire Zloh University of Hertfordshire

By | 12th June 2017

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Mire Zloh University of Hertfordshire

Mire Zloh University of Hertfordshire

Professor Mire Zloh

Mire Zloh

Professor Mire Zloh

Professor

Postal address:
University of Hertfordshire, Hatfield, Hertfordshire
United Kingdom

Overview

Prof. Zloh has taken a position of the Head of Pharmaceutical Chemistry in the Department of Pharmacy in January 2013. He is currently on secondment within the Centre for Health Services and Clinical Research.

Prior to his present position was Senior Lecturer at the UCL School of Pharmacy and was responsible for the integrated structural chemistry service that provides NMR, MS and CHN analysis to internal and external users. He was an Assistant Professor at the Faculty of Pharmacy in Belgrade for the Clinical Chemistry Instrumentation course before moving to London. From 2002 to 2003, he was a tutor counsellor for the Open University. Prof. Zloh was Deputy Director on the MSc Course in Drug Discovery at UCL School of Pharmacy.

Prof. Zloh has continued collaborations with Professors Simon Gibbons, Steve Brocchini, Stephen Neidle, Drs John Malkinson, Geoff Wells and Paul Stapleton at the UCL  School of Pharmacy. He has external collaborations with Professors Ivan Juranic, Tatjana Verbic, Slavica Eric and Vladirmir Savic (University of Belgrade), Dr Petros Tsoungas (Greece), Professor Laurence Patterson (University of Bradford), Professor Rogério Gaspar (University of Lisbon) and Professor Deniz Tasdemir (National University of Ireland).

Prof. Mire Zloh graduated in Physical Chemistry from the University of Belgrade (Yugoslavia) in 1987. He was then awarded an MSc in Physical Chemistry from the same university in 1992. His research in structural biology resulted in a PhD in Chemistry from the University of London in 1998 with a thesis entitled “Conformational Studies of the High Affinity IgE Receptor Peptides and Domains by NMR and Molecular Modelling”.

He was elected as a Fellow of the Royal Society of Chemistryand he is a member of Academy of Pharmaceutical Sciences, Molecular Graphics and Modelling Society, Serbian Chemical Society and Society of Physical Chemists of Serbia. Prof. Zloh was serving as a membership secretary for the now defunct RSC Molecular Modelling interest group.

 

Professor Mire Zloh

Expertise

Research interests

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.

Teaching specialisms

Nuclear Magnetic Resonance (NMR) Spectroscopy, Structure Elucidation, Molecular Modelling, Computational Chemistry, Molecular Dynamics, QSAR, Chemometrics, Mechanism of anticancer MDR inhibition.