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Computer-assisted combinatorial design of bicyclic thymidine analogs as inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase

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Abstract

Thymidine monophosphate kinase (TMPKmt) is an essential enzyme for nucleotide metabolism in Mycobacterium tuberculosis, and thus an attractive target for novel antituberculosis agents. In this work, we have explored the chemical space around the 2′,3′-bicyclic thymidine nucleus by designing and in silico screening of a virtual focused library selected via structure based methods to identify more potent analogs endowed with favorable ADME-related properties. In all the library members we have exchanged the ribose ring of the template with a cyclopentane moiety that is less prone to enzymatic degradation. In addition, we have replaced the six-membered 2′,3′-ring by a number of five-membered and six-membered heterocyclic rings containing alternative proton donor and acceptor groups, to exploit the interaction with the carboxylate groups of Asp9 and Asp163 as well as with several cationic residues present in the vicinity of the TMPKmt binding site. The three-dimensional structure of the TMPKmt complexed with 5-hydroxymethyl-dUMP, an analog of dTMP, was employed to develop a QSAR model, to parameterize a scoring function specific for the TMPKmt target and to select analogues which display the highest predicted binding to the target. As a result, we identified a small highly focused combinatorial subset of bicyclic thymidine analogues as virtual hits that are predicted to inhibit the mycobacterial TMPK in the submicromolar concentration range and to display favorable ADME-related properties.

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Abbreviations

ADME:

Adsorption, distribution, metabolism and excretion

AZTMP:

3′-azido-2′-deoxythymidine monophosphate

CFF91:

Consistent class II force field

dTTP:

Deoxythymidine triphosphate

dUMP:

Deoxyuridine monophosphate

HB:

Hydrogen bond

TEM:

5′-CH2OH dUMP inhibitor

TMPKh :

Human thymidine monophosphate kinase

TMPKmt :

Mycobacterium tuberculosis thymidine monophosphate kinase

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Acknowledgments

This work has been done within the ICS-UNIDO global program on Rational Drug Design and Discovery. Overall support of this work by ICS-UNIDO is gratefully acknowledged. We thank to Dr. Eugene Megnassan for technical assistance.

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Authors and Affiliations

  1. International Centre for Science and High Technology, UNIDO, AREA Science Park, Padriciano 99, 34012, Trieste, Italy

    Vladimir Frecer, Pierfausto Seneci & Stanislav Miertus

  2. Cancer Research Institute, Slovak Academy of Sciences, 83391, Bratislava, Slovakia

    Vladimir Frecer

  3. Department of Physical Chemistry of Drugs, Faculty of Pharmacy, Comenius University, 83232, Bratislava, Slovakia

    Vladimir Frecer

  4. Department of Organic and Industrial Chemistry and CISI, University of Milan, 20133, Milan, Italy

    Pierfausto Seneci

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  1. Vladimir Frecer
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Correspondence to Stanislav Miertus.

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Frecer, V., Seneci, P. & Miertus, S. Computer-assisted combinatorial design of bicyclic thymidine analogs as inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase. J Comput Aided Mol Des 25, 31–49 (2011). https://doi.org/10.1007/s10822-010-9399-4

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