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Prof Mire Zloh
UCL School of Pharmacy
29-39 Brunswick Square
London
UK
WC1N 1AX
Appointment
  • Visiting Professor
  • UCL School of Pharmacy
  • Faculty of Life Sciences
Biography

Mire Zloh is a Honorary Professor at the UCL School of Pharmacy. He was the Head of Pharmaceutical Chemistry in the Department of Pharmacy at the University of Hertfordshire and Research Professor within the Centre for Health Services and Clinical Research from January 2013 until September 2017. He is Emeritus Professor of Medicinal Chemistry at the University of Hertfordshire.

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 Helena Florindo (University of Lisbon) and Professor Liping Wang (Nanjing Agricultural University, China).

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 Chemistry and he is a member of Academy of Pharmaceutical Sciences.
Research Summary

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.

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.

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