Computational Analysis of Amiloride Analogue Inhibitors of Coxsackie Virus B3 RNA Polymerase
- *Corresponding Author:
- Jessica K Holien
Structural Biology Laboratory and ACRF Rational Drug Discovery Centre
St. Vincent’s Institute of Medical Research
9 Princes St, Fitzroy, Victoria 3065, Australia
Tel: (+61-3) 9288 2480
E-mail: [email protected]
Received date: June 26, 2014; Accepted date: July 28, 2014; Published date: August 02, 2014
Citation: Holien JK, Gazina EV, Elliott RW, Jarrott B, Cameron CE, et al. (2014) Computational Analysis of Amiloride Analogue Inhibitors of Coxsackievirus B3 RNA Polymerase. J Proteomics Bioinform S9:004. doi: 10.4172/jpb.S9-004
Copyright: © 2014 Holien JK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Coxsackie virus B3 (CVB3) is a picorna virus that is responsible for a significant proportion of human myocarditis. However, no antiviral treatment is currently available to treat this disease or indeed any picorna viral infections. Previously it was shown that amiloride and its derivative 5-(N-ethyl-N-isopropyl) amiloride inhibit the in vitro enzymatic activity of CVB3 RNA polymerase (3Dpol). Here we measure and compare the inhibitory activity of ten amiloride analogues against CVB3 3Dpol. We show that replacement of the 3,5-diaminopyrazinyl moiety of amiloride causes loss of the inhibitory activity, whereas modifications at the 5-amino and guanidino groups increase or decrease potency. Importantly, a combination of substitutions at both the 5-amino and guanidino groups produced a compound that was more potent than its singly modified precursors. The compounds were computationally-docked into available crystal structures of CVB3 3Dpol in order to obtain a structural explanation for the activities of the analogues. To create a robust model which explained the biological activity, optimization of one of the CVB3 3Dpol crystal structures to take into account active site flexibility was necessary, together with the use of consensus docking from two different docking algorithms. This robust predictive 3D atomic model provides insights into the interactions required for inhibitor binding and provides a promising basis for the development of more potent inhibitors against this important therapeutic target.