Shozeb Haider

Computational Studies of G-Quadruplex Complexes
We are interested in applying computational methods including multi-nanosecond molecular dynamics simulations to G-quadruplex complexes from telomeric and non-telomeric DNA. There has been a recent increase in identification of several topologies unique to G-quadruplex sequences. Studying conformational dynamics is essential in understanding the chemical environment for new ligand design.

Structure-based Drug Designing
The aim of the project is to search various databases for ligand molecules that could act as potential G-quadruplex stabilisers. Small molecules once identified are then worked upon to improve their design to generate Lead molecules with higher specificity and lower cytotoxicity.

Structural Studies of G-Quadruplexes (possibly with ligands)
Crystallisation and Structural determination of various G-quadruplexes (native and complexes) using potential G-quadruplex forming sequences occurring across the genome. Previous structures include telomeric G-quadruplexes from Oxytricha and in complex with a telomerase inhibitor.

Computational Studies of Inwardly Rectifying K+ Channels
(with Prof. Mark Sansom and Prof. Frances Ashcroft, The University of Oxford)
Inwardly rectifying Kir6.2 K+ channels plays a central role in secretion of insulin in the B-cells of the pancreas. We have successfully identified the binding sites for ATP and PIP2 on Kir6.2 K+ channel. Studying the conformational dynamics in the presence of natural ligands would help us understand the gating phenomenon that is central to the functioning of these channels. This information can be used to design small molecules that would interfere with this process and thereby modulating the activity of the channel. A much needed boost to therapeutics of diabetic patients.

PUBLICATIONS

• Haider, S., Tarasov, A., Craig, T., Sansom, M.S.P. and Ashcroft, F. (2007). Identification of PIP2-binding site on Kir6.2 by Molecular Modelling and Functional Analysis. EMBO. J. In Press
• Haider, S., Rapedius, M., Browne, K.F., Shang, L., Sansom, M.S.P., Baukrowitz, T. and Tucker, S.J. (2006). Structural and Functional Analysis of the putative pH-sensor in the Kir1.1 (ROMK) Potassium Channel. EMBO. Reports 7(6): 611-617
• Haider, S., Antcliff, J., Proks, P., Sansom, M.S.P. and Ashcroft, F. (2005). Functional Analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit. EMBO. J. 24(2): 229-239
• Proks, P., Girard, C, Haider, S., Golyn, A., Hattersely, A. Sansom, M.S.P. and Ashcroft, F.M. (2005). A novel gating mutation at the internal mouth of the Kir6.2 pore associated with DEND syndrome. EMBO reports 6(5): 470-475
• Trapp, S., Haider, S., Jones,P. Sansom, M.S.P. and Ashcroft, F. (2003). Identification of residues contributing to the ATP-binding site of Kir 6.2. EMBO. J. 22(12): 2903-2912
• Haider, S., Parkinson, G. and Neidle, S. (2003). Crystal Structure of the G-Quadruplex DNA-Drug complex. J. Mol. Biol. 326(1): 117-125
• Haider, S., Parkinson, G. and Neidle, S. (2002). Crystal structure of the potassium form of a Oxytricha nova G-Quadruplex. J. Mol. Biol. 320(2): 189-200