Int. J. Mol. Sci. 2014, 15(2), 3253-3261; doi:10.3390/ijms15023253
Communication

Rationalization of Activity Cliffs of a Sulfonamide Inhibitor of DNA Methyltransferases with Induced-Fit Docking

1,* email, 2email and 3email
Received: 14 January 2014; in revised form: 12 February 2014 / Accepted: 14 February 2014 / Published: 21 February 2014
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract: Inhibitors of human DNA methyltransferases (DNMT) are of increasing interest to develop novel epi-drugs for the treatment of cancer and other diseases. As the number of compounds with reported DNMT inhibition is increasing, molecular docking is shedding light to elucidate their mechanism of action and further interpret structure–activity relationships. Herein, we present a structure-based rationalization of the activity of SW155246, a distinct sulfonamide compound recently reported as an inhibitor of human DNMT1 obtained from high-throughput screening. We used flexible and induce-fit docking to develop a binding model of SW155246 with a crystallographic structure of human DNMT1. Results were in excellent agreement with experimental information providing a three-dimensional structural interpretation of ‘activity cliffs’, e.g., analogues of SW155246 with a high structural similarity to the sulfonamide compound, but with no activity in the enzymatic assay.
Keywords: drug design; enzyme inhibition; epigenetics; induced-fit docking; protein–ligand interactions
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MDPI and ACS Style

Medina-Franco, J.L.; Méndez-Lucio, O.; Yoo, J. Rationalization of Activity Cliffs of a Sulfonamide Inhibitor of DNA Methyltransferases with Induced-Fit Docking. Int. J. Mol. Sci. 2014, 15, 3253-3261.

AMA Style

Medina-Franco JL, Méndez-Lucio O, Yoo J. Rationalization of Activity Cliffs of a Sulfonamide Inhibitor of DNA Methyltransferases with Induced-Fit Docking. International Journal of Molecular Sciences. 2014; 15(2):3253-3261.

Chicago/Turabian Style

Medina-Franco, José L.; Méndez-Lucio, Oscar; Yoo, Jakyung. 2014. "Rationalization of Activity Cliffs of a Sulfonamide Inhibitor of DNA Methyltransferases with Induced-Fit Docking." Int. J. Mol. Sci. 15, no. 2: 3253-3261.

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