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J Biol Chem. 2018 Jun 22;293(25):9696-9705. doi: 10.1074/jbc.RA118.002588. Epub 2018 May 8.

A computational approach for predicting off-target toxicity of antiviral ribonucleoside analogues to mitochondrial RNA polymerase.

Author information

1
From the Li Ka Shing Applied Virology Institute, Department of Medical Microbiology and Immunology and hfreedma@ualberta.ca.
2
the Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2R7, Canada.
3
the Department of Physics, University of Alberta, Edmonton, Alberta T6G 2E1, Canada and.
4
From the Li Ka Shing Applied Virology Institute, Department of Medical Microbiology and Immunology and.
5
From the Li Ka Shing Applied Virology Institute, Department of Medical Microbiology and Immunology and mhoughto@ualberta.ca.

Abstract

In the development of antiviral drugs that target viral RNA-dependent RNA polymerases, off-target toxicity caused by the inhibition of the human mitochondrial RNA polymerase (POLRMT) is a major liability. Therefore, it is essential that all new ribonucleoside analogue drugs be accurately screened for POLRMT inhibition. A computational tool that can accurately predict NTP binding to POLRMT could assist in evaluating any potential toxicity and in designing possible salvaging strategies. Using the available crystal structure of POLRMT bound to an RNA transcript, here we created a model of POLRMT with an NTP molecule bound in the active site. Furthermore, we implemented a computational screening procedure that determines the relative binding free energy of an NTP analogue to POLRMT by free energy perturbation (FEP), i.e. a simulation in which the natural NTP molecule is slowly transformed into the analogue and back. In each direction, the transformation was performed over 40 ns of simulation on our IBM Blue Gene Q supercomputer. This procedure was validated across a panel of drugs for which experimental dissociation constants were available, showing that NTP relative binding free energies could be predicted to within 0.97 kcal/mol of the experimental values on average. These results demonstrate for the first time that free-energy simulation can be a useful tool for predicting binding affinities of NTP analogues to a polymerase. We expect that our model, together with similar models of viral polymerases, will be very useful in the screening and future design of NTP inhibitors of viral polymerases that have no mitochondrial toxicity.

KEYWORDS:

RNA polymerase; antiviral agent; computation; computer modeling; mitochondria; mitochondrial RNA polymerase; molecular dynamics; molecular modeling; nucleoside/nucleotide analogue; nucleotide

PMID:
29739852
PMCID:
PMC6016467
[Available on 2019-06-22]
DOI:
10.1074/jbc.RA118.002588
[Indexed for MEDLINE]

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