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QSAR-driven rational design of novel DNA methyltransferase 1 inhibitors.

ABSTRACT: DNA methylation, an epigenetic modification, is mediated by DNA methyltransferases (DNMTs), a family of enzymes. Inhibitions of these enzymes are considered a promising strategy for the treatment of several diseases. In this study, a quantitative structure-activity relationship (QSAR) modeling was employed to understand the structure-activity relationship (SAR) of currently available non-nucleoside DNMT1 inhibitors (i.e., indole and oxazoline/1,2-oxazole scaffolds). Two QSAR models were successfully constructed using multiple linear regression (MLR) and provided good predictive performance (R2 Tr = 0.850-0.988 and R2 CV = 0.672-0.869). Bond information content index (BIC1) and electronegativity (R6e+) are the most influential descriptors governing the activity of compounds. The constructed QSAR models were further applied for guiding a rational design of novel inhibitors. A novel set of 153 structurally modified compounds were designed in silico according to the important descriptors deduced from the QSAR finding, and their DNMT1 inhibitory activities were predicted. This result demonstrated that 86 newly designed inhibitors were predicted to elicit enhanced DNMT1 inhibitory activity when compared to their parent compounds. Finally, a set of promising compounds as potent DNMT1 inhibitors were highlighted to be further developed. The key SAR findings may also be beneficial for structural optimization to improve properties of the known inhibitors.

SUBMITTER: Phanus-Umporn C

PROVIDER: S-EPMC7214779 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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QSAR-driven rational design of novel DNA methyltransferase 1 inhibitors.

Phanus-Umporn Chuleeporn C Prachayasittikul Veda V Nantasenamat Chanin C Prachayasittikul Supaluk S Prachayasittikul Virapong V

EXCLI journal 20200402

DNA methylation, an epigenetic modification, is mediated by DNA methyltransferases (DNMTs), a family of enzymes. Inhibitions of these enzymes are considered a promising strategy for the treatment of several diseases. In this study, a quantitative structure-activity relationship (QSAR) modeling was employed to understand the structure-activity relationship (SAR) of currently available non-nucleoside DNMT1 inhibitors (i.e., indole and oxazoline/1,2-oxazole scaffolds). Two QSAR models were successf ...[more]

PMID: 32398970

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Project description:Treatment of several autoimmune diseases and types of cancer has been an intense area of research over the past two decades. Many signaling pathways that regulate innate and/or adaptive immunity, as well as those that induce overexpression or mutation of protein kinases, have been targeted for drug discovery. One of the serine/threonine kinases, Interleukin-1 Receptor Associated Kinase 4 (IRAK4) regulates signaling through various Toll-like receptors (TLRs) and interleukin-1 receptor (IL1R). It controls diverse cellular processes including inflammation, apoptosis, and cellular differentiation. MyD88 gain-of-function mutations or overexpression of IRAK4 has been implicated in various types of malignancies such as Waldenström macroglobulinemia, B cell lymphoma, colorectal cancer, pancreatic ductal adenocarcinoma, breast cancer, etc. Moreover, over activation of IRAK4 is also associated with several autoimmune diseases. The significant role of IRAK4 makes it an interesting target for the discovery and development of potent small molecule inhibitors. A few potent IRAK4 inhibitors such as PF-06650833, RA9 and BAY1834845 have recently entered phase I/II clinical trial studies. Nevertheless, there is still a need of selective inhibitors for the treatment of cancer and various autoimmune diseases. A great need for the same intrigued us to perform molecular modeling studies on 4,6-diaminonicotinamide derivatives as IRAK4 inhibitors. We performed molecular docking and dynamics simulation of 50 ns for one of the most active compounds of the dataset. We also carried out MM-PBSA binding free energy calculation to identify the active site residues, interactions of which are contributing to the total binding energy. The final 50 ns conformation of the most active compound was selected to perform dataset alignment in a 3D-QSAR study. Generated RF-CoMFA (q2 = 0.751, ONC = 4, r2 = 0.911) model revealed reasonable statistical results. Overall results of molecular dynamics simulation, MM-PBSA binding free energy calculation and RF-CoMFA model revealed important active site residues of IRAK4 and necessary structural properties of ligand to design more potent IRAK4 inhibitors. We designed few IRAK4 inhibitors based on these results, which possessed higher activity (predicted pIC50) than the most active compounds of the dataset selected for this study. Moreover, ADMET properties of these inhibitors revealed promising results and need to be validated using experimental studies.

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QSAR-driven rational design of novel DNA methyltransferase 1 inhibitors.

Publications

QSAR-driven rational design of novel DNA methyltransferase 1 inhibitors.

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