Predictive computational models of substrate binding by a nucleoside transporter

Collar, C.J., Al Salabi, M.I., Stewart, M.L., Barrett, M.P. , Wilson, W.D. and de Koning, H.P. (2009) Predictive computational models of substrate binding by a nucleoside transporter. Journal of Biological Chemistry, 284(49), pp. 34028-34035. (doi:10.1074/jbc.M109.049726)

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Transporters play a vital role in both the resistance mechanisms of existing drugs and effective targeting of their replacements. Melarsoprol and diamidine compounds similar to pentamidine and furamidine are primarily taken up by trypanosomes of the genus Trypanosoma brucei through the P2 aminopurine transporter. In standardized competition experiments with [H-3] adenosine, P2 transporter inhibition constants (K-i) have been determined for a diverse dataset of adenosine analogs, diamidines, Food and Drug Administration-approved compounds and analogs thereof, and custom-designed trypanocidal compounds. Computational biology has been employed to investigate compound structure diversity in relation to P2 transporter interaction. These explorations have led to models for inhibition predictions of known and novel compounds to obtain information about the molecular basis for P2 transporter inhibition. A common pharmacophore for P2 transporter inhibition has been identified along with other key structural characteristics. Our model provides insight into P2 transporter interactions with known compounds and contributes to strategies for the design of novel antiparasitic compounds. This approach offers a quantitative and predictive tool for molecular recognition by specific transporters without the need for structural or even primary sequence information of the transport protein

Item Type:Articles
Glasgow Author(s) Enlighten ID:De Koning, Professor Harry and Barrett, Professor Michael
Authors: Collar, C.J., Al Salabi, M.I., Stewart, M.L., Barrett, M.P., Wilson, W.D., and de Koning, H.P.
Subjects:Q Science > QP Physiology
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Biological Chemistry
Journal Abbr.:J Biol Chem.
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN (Online):1083-351X
Published Online:05 October 2009

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
522031In vivo imaging models of African trypanosomiasis to support drug discovery programmes.Michael BarrettGates Foundation (GATES)OPPGH5337III - PARASITOLOGY