David (Dai) Hibbs

Associate Professor in Pharmaceutical Sciences

Career Profile

Bsc. (Hons) Chemistry, University of Wales Cardiff, 1989-1992.
PhD Chemistry, Cardiff University, 1998.
Postdoctoral Fellow, Cardiff University, 1998.
Royal Society Fellow, University of Sydney, 1999.
NH&MRC Research Scientist, University of Sydney, 2000.
ARC Postdoctoral Fellow, University of Sydney, 2001.
University of Sydney Fellow, 2004.
ARC Research Fellow, University of Sydney, 2005.

Contact Details

University of Sydney
Phone: +61 2 9351 6005
Fax: +61 2 9351 4391
Email:
Room 500
Badham Building A16
The University of Sydney
NSW 2006 Australia

Research Interests

Molecular Modelling and Computational Chemistry
Biological and Medicinal Chemistry
Drug Design
Solid state chemistry
High resolution X-ray and neutron diffraction.
Experimental charge density distributions. ab initio and DFT calculations.

Solid State Methods in Drug Design
(M. Waller, N. Salam, Thanh Ha Nguyen)

The development of compounds that are effective in the treatment of neurological disorders and have less side effects than existing drugs depends upon selective drug/target interactions. A knowledge of the factors which influence molecular recognition and binding in drug/receptor complexes is of paramount importance when designing more effective drugs.

In this project we aim to develop a quantitative measure of intermolecular interaction energies in model drug/target systems. These results are then used to tune the properties of two novel classes of selective anti-anxiolytic drugs and thereby develop agents able to treat diseases such as epilepsy, schizophrenia, depression and memory disorders

Design, synthesis and pharmacology of kynurenine aminotransferase I Inhibitors
(N. Salam)

Human kynurenine aminotransferase 1 (hKAT-1) is responsible for the catalysis of l-kynurenine into kynureninc acid (KA) - a broad spectrum excitatory amino acid receptor antagonist. The importance of hKAT-1 in the central nervous system is highlighted by KA's implication in the development of schizophrenia1. High levels of KA found in the cerebral spinal fluid of schizophrenic patients signify the molecule's contribution in the pathogenesis of the disease, suggesting novel therapeutic strategies are to be directed towards the reduction of brain KA levels.

As such, hKAT-1 has been identified as a potential target for anti-psychotic drugs. The aims of this project are: (i) Design selective small-molecule inhibitors targeting hKAT-1 - utilizing the hKAT-1 crystal structure and computer-aided design strategies (ii) Chemically synthesize and/or purchase potential hit-to-lead compounds. (iii) Assay and evaluate the compounds hKAT-1 inhibition activity.

Flavonoids as modulators of GABA receptors
(Thanh Ha Nguyen, Dr Mary Collins, Dr Jane Hanrahan, Faculty of Pharmacy and Professor Graham Johnston, Department of Pharmacology)

The primary objective of this project is to contribute to the design and development of new drugs via a study of the experimental charge distribution in molecular crystals. This will initially involve the high resolution X-ray crystallographic study of a number of novel receptorial drugs of the flavonoid class, using a multipole refinement procedure to determine the electron distribution.
Flavonoids are polyphenolic compounds found extensively in plants, and recently, it has become clear that some flavonoids have effects on the central nervous system and it is this group that will be the subject of the project outlined here. GABA (g -aminobutyric acid) is the major inhibitory transmitter in the brain and it has been shown that the anxiolytic flavone apigenin has a novel mode of action on GABA receptors in the brain. This project seeks to relate the structural and electronic characteristics of this novel mode of action, and how flavonoids may influence actions of other molecules in order to design and develop potentially useful therapeutic agents for CNS disorders.

Experimental Charge Density Studies of Platinum Complexes
(M. Waller)

Platinum anticancer drugs such as cisplatin (cis-[PtCl2(NH3)2]) effect their action by binding to DNA. It has been suggested the incoming platinum complex recognises different sequences and that design of compounds capable of targeting different sequences will depend on the ability to model this recognition process. Before such modelling can be reliably undertaken, charge distributions of the platinum complexes need to be determined. Theoretical methods are available for producing charge distributions but they have had no experimental verification as yet. Therefore, an important goal of this project is to develop methods for determining the electronic distributions in platinum complexes of the type involved in binding to DNA.

Insights into Hydrogen Bonding
(M. Waller, Thanh Ha Nguyen; Dr Jacob Overgaard, Aarhus University Denmark)

The primary objective of this project is to contribute to the understanding of the nature of hydrogen bonding in biological systems via a study of the experimental electron distribution. The hydrogen bond is the most versatile intermolecular interaction in the biological and material worlds and is responsible for molecular aggregation, protein folding and enzyme activity. Conventionally strong hydrogen bonds such as O – H …O, N – H …O and O – H …N have been extensively exploited in the areas of supramolecular chemistry and crystal engineering. In contrast, the somewhat weaker N – H …N hydrogen bonds have been scarcely studied, but clearly have important roles in nature. For example, the gross structure of protein molecules, the structures of the genetically important DNA and RNA molecules, as well as drug – receptor binding.

Molecular Orbital Applications in X-ray diffraction
(M. Waller; Dr Sian Howard, University of South Australia)

Within our group we have developed a unique approach to analysing experimental charge density using a basis of (squared) molecular orbitals, as opposed to the multipole-based methods in common use. Such an alternative approach has certain advantages, including (i) providing a density which is constrained to be positive over all space (ii) access to a wider range of molecular properties (iii) the ability to treat noncentrosymmetric spacegroups more reliably.

This is particularly important for charge density studies of (chiral) natural products and drug molecules, which frequently crystallize in noncentrosymmetric space groups. This approach is implemented in the fortran program MOON (Molecular Orbital Occupation Number), a beta-test version which is freely available on

Current Grants

Experimental Electron Densities, Crystal Engineering and Molecular Recognition: A Supramolecular Approach to Drug Design - ARC 2005
Molecular Simulation of the Effects of Additives on Generation of Dry Powder Aerosols - University of Sydney R&D Grant Scheme 2005

Research Publications

2007

Experimental and Theoretical Charge Density Distribution in Two Ternary Cobalt(III) Complexes of Aromatic Amino Acids. Overgaard, Jacob; Waller, Mark P.; Piltz, Ross; Platts, James A.; Emseis, Paul; Leverett, Peter; Williams, Peter A.; Hibbs, David E. Journal of Physical Chemistry A (2007), 111(40), 10123-10133.
The structure of gillardite, the Ni-analogue of herbertsmithite, from Widgiemooltha, Western Australia. Clissold, Meagan E.; Leverett, Peter; Williams, Peter A.; Hibbs, David E.; Nickel, Ernest H. Canadian Mineralogist (2007), 45(2), 317-320.
Experimental electron density study of a complex between copper(ii) and the antibacterial quinolone family member ciprofloxacin. Overgaard, Jacob; Turel, Iztok; Hibbs, David E. Dalton Transactions (2007), (21), 2171-2178.
Synthesis and Characterization of Iron(II) Complexes of 10- and 11-Membered Triphosphamacrocycles. Battle, Andrew R.; Edwards, Peter G.; Haigh, Robert; Hibbs, David E.; Li, Dongmei; Liddiard, Sam M.; Newman, Paul D. Organometallics (2007), 26(2), 377-386.

2006

Review of main chain liquid crystalline polymers. Pavel, Dumitru; Hibbs, David; Shanks, Robert. Advanced Research in Polymer Science (2006), 65-84.
T-cell antigen receptor-alpha chain transmembrane peptides: correlation between structure and function. Ali, Marina; Salam, Noeris K.; Amon, Michael; Bender, Veronika; Hibbs, David E.; Manolios, Nicholas. International Journal of Peptide Research and Therapeutics (2006), 12(3), 261-267.
Platinum(IV) Analogues of AMD473 (cis-[PtCl2(NH3)(2-picoline)]): Preparative, Structural, and Electrochemical Studies. Battle, Andrew R.; Choi, Robin; Hibbs, David E.; Hambley, Trevor W. Inorganic Chemistry (2006), 45(16), 6317-6322.
Cholesterol effect on the dipole potential of lipid membranes. Starke-Peterkovic, Thomas; Turner, Nigel; Vitha, Mark F.; Waller, Mark P.; Hibbs, David E.; Clarke, Ronald J. Biophysical Journal (2006), 90(11), 4060-4070.
Hybrid density functional theory for  -stacking interactions: application to benzenes, pyridines, and DNA bases. Waller, Mark P.; Robertazzi, Arturo; Platts, James A.; Hibbs, David E.; Williams, Peter A. Journal of Computational Chemistry (2006), 27(4), 491-504.
Quantum-Chemical Design of Cryptand-like Ditopic Salt Binders. Howard, Sian T.; Hibbs, David E.; Amoroso, Angelo J.; Platts, James A. Journal of Chemical Theory and Computation(2006), 2(2), 354-363.
Novel properties from experimental charge densities: an application to the zwitterionic neurotransmitter taurine. Waller M P; Howard S T; Platts J A; Piltz R O; Willock D J; Hibbs D E. Chemistry (Weinheim an der Bergstrasse, Germany) (2006), 12(29), 7603-14.

2005

Conformations, energies, and intramolecular hydrogen bonds in dicarboxylic acids: Implications for the design of synthetic dicarboxylic acid receptors. Nguyen, Thanh Ha; Hibbs, David E.; Howard, Sian T. Journal of Computational Chemistry (2005), 26(12), 1233-1241.
A new orbital-based model for the analysis of experimental molecular charge densities: an application to (Z)-N-methyl-C-phenylnitrone. Hibbs, David E.; Howard, Sian T.; Huke, Jeremy P.; Waller, Mark P. Physical Chemistry Chemical Physics (2005), 7(8), 1772-1778.
Comparison of the structure property relationships in LB films of zwitterionic TCNQ adducts. Bell, Norman A.; Bradley, Christopher S.; Broughton, Richard A.; Coles, Simon J.; Hibbs, David E.; Hursthouse, Michael B.; Ray, Asim K.; Simmonds, Derek J.; Thorpe, Stephen C. Journal of Materials Chemistry (2005), 15(14), 1437-1445.
Silver acetate-catalyzed asymmetric 1,3-dipolar cycloadditions of imines and chiral acrylamides. Nyerges, Miklos; Bendell, David; Arany, Andrea; Hibbs, David E.; Coles, Simon J.; Hursthouse, Michael B.; Groundwater, Paul W.; Meth-Cohn, Otto. Tetrahedron (2005), 61(15), 3745-3753.
Imidazolium formation from the reaction of N-heterocyclic carbine stabilised group 13 trihydride complexes with organic acids.Cole, Marcus L.; Hibbs, David E.; Jones, Cameron; Junk, Peter C.; Smithies, Neil A. Inorganica Chimica Acta (2005), 358(7), 2455.
Experimental charge density of a potential DHO synthetase inhibitor: dimethyl-trans-2-oxohexahydro-pyrimidine-4,6-dicarboxylate.Hibbs, David E.; Overgaard, Jacob; Howard, Sian T.; Nguyen, Thanh Ha. Organic & Biomolecular Chemistry (2005), 3(3), 441-447.
Imidazolium formation from the reaction of N-heterocyclic carbene stabilised group 13 trihydride complexes with organic acids. Cole, Marcus L.; Hibbs, David E.; Jones, Cameron; Junk, Peter C.; Smithies, Neil A. Inorganica Chimica Acta (2005), 358(1), 102-108.

2004

The experimental electron density in polymorphs A and B of the anti-ulcer drug famotidine.Overgaard, Jacob; Hibbs, David E. Acta Crystallographica, Section A: Foundations of Crystallography (2004), A60(5), 480-487.
The structure of L -b 1-[Co(R,R-picchxn)(S-tyr)]Br2× 3.5H2O and solution configuration of L -b 1-[Co(R,R-picchxn)(aromatic S-aminoacidate)]2+ complexes: model systems for the investigation of non-covalent aromatic interactions. Emseis, Paul; Hibbs, David E.; Leverett, Peter; Reddy, Narsimha; Williams, Peter A. Inorganica Chimica Acta (2004), 357(11), 3251-3263.
Weak intramolecular interactions in perchlorate salts of L -b1-[Co(R,R-picchxn)(R-aa)]2+[picchxn=N,N'-di(2-picolyl)-1,2-diaminocyclohexane; aa = phenylalaninato(1-), tyrosinato(1-)] and their diastereoisomeric equilibration in solution. Emseis, Paul; Hibbs, David E.; Leverett, Peter; Reddy, Narsimha; Williams, Peter A. Inorganica Chimica Acta (2004), 357(9), 2669-2676.
Intramolecular NH-p and p -p interactions in ternary cobalt(III) complexes of aromatic aminoacids: a structural and NMR study. Emseis, Paul; Failes, Timothy W.; Hibbs, David E.; Leverett, Peter; Williams, Peter A. Polyhedron (2004), 23(10), 1749-1767.
Synthesis and resolution of 2-methyl analogs of GABA. Duke, Rujee K.; Chebib, Mary; Hibbs, David E.; Mewett, Kenneth N.; Johnston, Graham A. R. Tetrahedron: Asymmetry (2004), 15(11), 1745-1751.
Studies on pyridazine azide cyclisation reactions. Allan, Robin D.; Greenwood, Jeremy R.; Hambley, Trevor W.; Hanrahan, Jane R.; Hibbs, David E.; Itani, Samia; Tran, Hue W.; Turner, Peter. Organic & Biomolecular Chemistry (2004), 2(12), 1782-1788.
Experimental and Theoretical Charge Density Studies of Tetrafluorophthalonitrile and Tetrafluoroisophthalonitrile. Hibbs, David E.; Overgaard, Jacob; Platts, James A.; Waller, Mark P.; Hursthouse, Michael B. Journal of Physical Chemistry B (2004), 108(11), 3663-3672.

The University of Sydney - Faculty of Pharmacy