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.
Highlights
DNA methyltransferases (DNMTs) are a family of enzymes that catalyze the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the carbon-5 position of cytosine residues, leading to an epigenetic modification [1]
A focused structure-activity relationship (SAR) analysis showed that the hydroxyl group of SW155246 was essential for its activity; loss of the hydroxyl group (SW155246-1) or addition of a methylated oxygen on the 1-position of the naphthyl ring (SW155246-2) (Figure 2) completely abolished the ability of this compound to inhibit human DNMT1 activity in vitro and reduced the cell-based cytotoxicity [13]
Docking of SW155246 and their structural analogues with human DNMT1 was preceded by validation of the docking approach
Summary
DNA methyltransferases (DNMTs) are a family of enzymes that catalyze the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the carbon-5 position of cytosine residues, leading to an epigenetic modification [1]. A focused structure-activity relationship (SAR) analysis showed that the hydroxyl group of SW155246 was essential for its activity; loss of the hydroxyl group (SW155246-1) or addition of a methylated oxygen on the 1-position of the naphthyl ring (SW155246-2) (Figure 2) completely abolished the ability of this compound to inhibit human DNMT1 activity in vitro and reduced the cell-based cytotoxicity [13]. This is an example of an ‘activity cliff” [14,15], i.e., a small change in the structure dramatically affects the biological activity.
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