Novel and selective DNA methyltransferase inhibitors: Docking-based virtual screening and experimental evaluation

Area of Science:

• Biochemistry
• Pharmacology
• Oncology

Background:

• DNA methyltransferases (DNMTs) are crucial epigenetic regulators and promising anticancer drug targets.
• Current DNMT inhibitors are non-selective cytosine analogues with significant cytotoxic side effects.
• Development of selective inhibitors for individual DNMT enzymes is needed.

Purpose of the Study:

• To identify novel small molecules with selective inhibition of human DNMT1.
• To discover compounds that bind to the active site of DNMT1, similar to the natural substrate.
• To provide tools for understanding the specific roles of DNMT enzymes in epigenetics and cancer.

Main Methods:

• Virtual screening of over 65,000 compounds from the National Cancer Institute (NCI) collection.
• Utilized a multistep docking approach with a validated homology model of human DNMT1 catalytic domain.
• Experimental evaluation of top-ranked virtual screening hits for DNMT1 and DNMT3B inhibition.

Main Results:

• Discovery of novel small molecules exhibiting potent DNMT1 inhibition.
• Identification of compounds with biochemical selectivity for DNMT1 over DNMT3B.
• These molecules bind to the same pocket as the native cytosine substrate, indicating a novel mechanism.

Conclusions:

• The identified small molecules are the first reported to show biochemical selectivity for an individual DNMT enzyme.
• These selective DNMT1 inhibitors represent promising candidates for rational optimization as anticancer drugs.
• Enzyme-selective inhibitors will advance the understanding of DNMT functions in epigenetic regulation and disease.