Title

Functional characterization of novel mutations in Ul54 of ganciclovir resistant HCMV strain using structural analysis 

Authors

Jambulingam Malathi¹, Vetrivel Umashankar², Ravichandran Sathyabaarathi², Sivashanmugan Muthukumaran², Murali Ishwarya¹, Hajib Narahari Madhavan¹*

Affiliation

¹Department of Microbiology, Vision Research Foundation, Sankara Nethralaya, Old no, 18, College Road, Chennai - 600 006, Tamilnadu, India; ²Centre for Bioinformatics, Vision Research Foundation, Sankara Nethralaya, Old no, 18, College Road, Chennai - 600 006, Tamilnadu, India 

Email

drhnm@snmail.org; *Corresponding author  

Phone

91-44-282716161

Fax

91 -44-28254180

Article Type

Hypothesis

Date

Received January 18, 2011; Accepted January 24, 2011; Published February 07, 2011
 

This study reports the probable impact of the coupled mutations observed in our clinical isolate of HCMV UL54 polymerase, through structural bioinformatics approaches. The reported variant was found to be resistant to Ganciclovir (GCV) as per the clinical records. The presence of Glutamine deletion at 639 (Glu639) and a mis sense mutation of Serine 655 Leucine (Ser655Leu) in UL54 were identified by DNA sequencing and were predicted to lie in the DNA polymerase type-II domain. Docking simulation studies of the phosphorylated forms of Ganciclovir (GCV), Cidofovir (CDV) and Foscarnet (PFA) with the reported mutants showed significant variation in terms of binding affinity and inhibitory constant (Ki) in comparison to wild type UL54. The findings of this study revealed that the observed coupled mutation could potentially induce allosteric effects in the binding pockets of UL54 and thereby alter the drug binding affinity. In specific, it was observed that this coupled mutation could confer changes in the binding affinity of GCV and PFA by altering the binding energies and inhibitory constants to -0.88Kcal/mol and 226.71mM, -5.81Kcal/mol and 54.83µM, respectively, in comparison to Wild Type. On the other hand, CDV showed increased susceptibility for the reported mutant with a binding energy of -6.16Kcal/mol and inhibitory constant of 30.47µM.  

Keywords

HCMV, UL54, GCV, Modeling, Docking, Drug resistance

Citation

Malathi et al. Bioinformation 5(9): 390-395 (2011)

Edited by

P Kangueane

ISSN

0973-2063

Publisher

Biomedical Informatics

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.