molecular dynamics

M_abualhasan's picture

Doing the Methylene Shuffle – Further Insights into the Inhibition of Mitotic Kinesin Eg5 with S-Trityl L-Cysteine

Journal Title, Volume, Page: 
European Journal of Medicinal Chemistry Volume 54, August 2012, Pages 483–498
Year of Publication: 
2012
Authors: 
Murad N. Abualhasan
Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, Scotland, UK
Current Affiliation: 
Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
James A.D. Good
The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, UK
Kitiyaporn Wittayanarakul
Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, Scotland, UK
Nahoum G. Anthony
Giacomo Berretta
Oliver Rath
The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, UK
Frank Kozielski
The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, UK
Oliver B. Sutcliffe
Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, Scotland, UK
Simon P. Mackay
Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, Scotland, UK
Preferred Abstract (Original): 

S-Trityl l-cysteine (STLC) is an inhibitor of the mitotic kinesin Eg5 with potential as an antimitotic chemotherapeutic agent. We previously reported the crystal structure of the ligand–protein complex, and now for the first time, have quantified the interactions using a molecular dynamics based approach. Based on these data, we have explored the SAR of the trityl head group using the methylene shuffle strategy to expand the occupation of one of the hydrophobic pockets. The most potent compounds exhibit strong (<100 nM) inhibition of Eg5 in the basal ATPase assay and inhibit growth in a variety of tumour-derived cell lines.

hasanalniss's picture

Ranking Ligand Affinity For The DNA Minor Groove By Experiment And Simulation

Journal Title, Volume, Page: 
American Chemical Society Med. Chem. Lett., 2010, 1 (8), pp 376–380 DOI: 10.1021/ml100047n
Year of Publication: 
2010
Authors: 
Hasan Y. Alniss
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, United Kingdom
Current Affiliation: 
Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
Simon P. MacKay
University of strathclyde, Glasgow, UK
John A. Parkinson
University of strathclyde, Glasgow, UK
Preferred Abstract (Original): 

The structural and thermodynamic basis for the strength and selectivity of the interactions of minor groove binders (MGBs) with DNA is not fully understood. In 2003, we reported the first example of a thiazole-containing MGB that bound in a phase-shifted pattern that spanned six base pairs rather than the usual four (for tricyclic distamycin-like compounds). Since then, using DNA footprinting, NMR spectroscopy, isothermal titration calorimetry, and molecular dynamics, we have established that the flanking bases around the central four being read by the ligand have subtle effects on recognition. We have investigated the effect of these flanking sequences on binding and the reasons for the differences and established a computational method to rank ligand affinity against varying DNA sequences.

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