Discovery of Novel and Selective Dna Methyltransferase 1 Inhibitors by Pharmacophore and Docking-Based Virtual Screening

Discovery of Novel and Selective Dna Methyltransferase 1 Inhibitors by Pharmacophore and Docking-Based Virtual Screening Publisher

Hassanzadeh M¹ ; Kasymov R² ; Mahernia S¹ ; Adib M³ ; Emperle M² ; Dukatz M² ; Bashtrykov P² ; Jeltsch A² ; Amanlou M¹

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1. Department of Medicinal Chemistry & Drug Design and Development Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, 16 Azar Ave., Tehran, Iran
2. Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University Stuttgart, Allmandring 31, Stuttgart, 70569, Germany
3. School of Chemistry, College of Science, University of Tehran, Tehran, Iran

Source: ChemistrySelect Published:2017

Abstract

Abnormal DNA methylation has key roles in the development and progression of diseases including cancer. Mechanism based DNA methyltransferase (DNMT) inhibitors (DNMTi) which inhibit all DNMTs, like 5-azacytidine and decitabine, are in clinical use for the treatment of acute myeloid leukemia and myelodysplastic syndrome. However, selective inhibitors for specific DNMTs may improve therapy and would be very useful in basic research. Targeting the binding pocket of DNMT1 for the flipped target base, we employed pharmacophore modeling based on known nucleoside-derived DNMTi followed by virtual screening of 500 compounds and docking studies for selection of potential DNMT1 inhibitors. DNMT inhibition assays with selected compounds led to the discovery of novel small molecule scaffolds with a high DNMT1 inhibitory potency. Compound 4b selectively inhibits DNMT1 with Ki in the low micromolar range while inhibition of DNMT3 enzymes is at least 50-fold weaker. Analysis of the inhibitory mechanism revealed non-competitive inhibition with the DNA and mixed with S-adenosyl-L-methionine in good agreement with the mode of action predicted from virtual screening. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Style	Citing Format
MLA	Hassanzadeh M, et al.. "Discovery of Novel and Selective Dna Methyltransferase 1 Inhibitors by Pharmacophore and Docking-Based Virtual Screening." ChemistrySelect, vol. 2, no. 27, 2017, pp. 8383-8392.
APA	Hassanzadeh M, Kasymov R, Mahernia S, Adib M, Emperle M, Dukatz M, Bashtrykov P, Jeltsch A, Amanlou M (2017). Discovery of Novel and Selective Dna Methyltransferase 1 Inhibitors by Pharmacophore and Docking-Based Virtual Screening. ChemistrySelect, 2(27), 8383-8392.
Chicago	Hassanzadeh M, Kasymov R, Mahernia S, Adib M, Emperle M, Dukatz M, Bashtrykov P, Jeltsch A, Amanlou M. "Discovery of Novel and Selective Dna Methyltransferase 1 Inhibitors by Pharmacophore and Docking-Based Virtual Screening." ChemistrySelect 2, no. 27 (2017): 8383-8392.
Harvard	Hassanzadeh M et al. (2017) 'Discovery of Novel and Selective Dna Methyltransferase 1 Inhibitors by Pharmacophore and Docking-Based Virtual Screening', ChemistrySelect, 2(27), pp. 8383-8392.
Vancouver	Hassanzadeh M, Kasymov R, Mahernia S, Adib M, Emperle M, Dukatz M, et al.. Discovery of Novel and Selective Dna Methyltransferase 1 Inhibitors by Pharmacophore and Docking-Based Virtual Screening. ChemistrySelect. 2017;2(27):8383-8392.
BibTex	@article{ author = {Hassanzadeh M and Kasymov R and Mahernia S and Adib M and Emperle M and Dukatz M and Bashtrykov P and Jeltsch A and Amanlou M}, title = {Discovery of Novel and Selective Dna Methyltransferase 1 Inhibitors by Pharmacophore and Docking-Based Virtual Screening}, journal = {ChemistrySelect}, volume = {2}, number = {27}, pages = {8383-8392}, year = {2017} }
RIS	TY - JOUR AU - Hassanzadeh M AU - Kasymov R AU - Mahernia S AU - Adib M AU - Emperle M AU - Dukatz M AU - Bashtrykov P AU - Jeltsch A AU - Amanlou M TI - Discovery of Novel and Selective Dna Methyltransferase 1 Inhibitors by Pharmacophore and Docking-Based Virtual Screening JO - ChemistrySelect VL - 2 IS - 27 SP - 8383 EP - 8392 PY - 2017 ER -

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