Fragment-based discovery of new potential DNMT1 inhibitors integrating multiple pharmacophore modeling, 3D-QSAR, virtual screening, molecular docking, ADME, and molecular dynamics simulation approaches

Goverdhan Lanka; Suvankar Banerjee; Nilanjan Adhikari; Balaram Ghosh

doi:10.1007/s11030-024-10837-5

Fragment-based discovery of new potential DNMT1 inhibitors integrating multiple pharmacophore modeling, 3D-QSAR, virtual screening, molecular docking, ADME, and molecular dynamics simulation approaches

Mol Divers. 2024 Apr 18. doi: 10.1007/s11030-024-10837-5. Online ahead of print.

Authors

Goverdhan Lanka^{1

2}, Suvankar Banerjee³, Nilanjan Adhikari³, Balaram Ghosh^{4

5}

Affiliations

¹ Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad, 500078, India.
² Computer Aided Drug Design Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad, 500078, India.
³ Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P. O. Box 17020, Kolkata, West Bengal, 700032, India.
⁴ Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad, 500078, India. balaram@hyderabad.bits-pilani.ac.in.
⁵ Computer Aided Drug Design Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad, 500078, India. balaram@hyderabad.bits-pilani.ac.in.

PMID: 38637479
DOI: 10.1007/s11030-024-10837-5

Abstract

DNA methyl transferases (DNMTs) are one of the crucial epigenetic modulators associated with a wide variety of cancer conditions. Among the DNMT isoforms, DNMT1 is correlated with bladder, pancreatic, and breast cancer, as well as acute myeloid leukemia and esophagus squamous cell carcinoma. Therefore, the inhibition of DNMT1 could be an attractive target for combating cancers and other metabolic disorders. The disadvantages of the existing nucleoside and non-nucleoside DNMT1 inhibitors are the main motive for the discovery of novel promising inhibitors. Here, pharmacophore modeling, 3D-QSAR, and e-pharmacophore modeling of DNMT1 inhibitors were performed for the large fragment database screening. The resulting fragments with high dock scores were combined into molecules. The current study revealed several constitutional pharmacophoric features that can be essential for selective DNMT1 inhibition. The fragment docking and virtual screening identified 10 final hit molecules that exhibited good binding affinities in terms of docking score, binding free energies, and acceptable ADME properties. Also, the modified lead molecules (GL1b and GL2b) designed in this study showed effective binding with DNMT1 confirmed by their docking scores, binding free energies, 3D-QSAR predicted activities and acceptable drug-like properties. The MD simulation studies also suggested that leads (GL1b and GL2b) formed stable complexes with DNMT1. Therefore, the findings of this study can provide effective information for the development/identification of novel DNMT1 inhibitors as effective anticancer agents.

Keywords: 3D-QSAR; ADME; Binding free energies; Bioisosterism; DNMT1; MD simulations; Molecular docking; Pharmacophore modeling; R-group enumeration; e-pharmacophore modeling.

Abstract

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