Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 15, Issue 2, Pages 3253-3261Publisher
MDPI
DOI: 10.3390/ijms15023253
Keywords
drug design; enzyme inhibition; epigenetics; induced-fit docking; protein-ligand interactions
Funding
- CONACyT [217442/312933]
- Cambridge Overseas Trust
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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.
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