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Pharmacophore-based virtual screening of ZINC database, molecular modeling and designing new derivatives as potential HDAC6 inhibitors

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Abstract

To date, many HDAC6 inhibitors have been identified and developed but none is clinically approved as of now. Through this study, we aim to obtain novel HDAC6 selective inhibitors and provide new insights into the detailed structural design of potential HDAC6 inhibitors. A HypoGen-based 3D QSAR HDAC6 pharmacophore was built and used as a query model to screen approximately 8 million ZINC database compounds. First, the ZINC Database was filtered using ADMET, followed by pharmacophore-based library screening. Using fit value and estimated activity cutoffs, a final set of 54 ZINC hits was obtained that were further investigated using molecular docking with the crystal structure of human histone deacetylase 6 catalytic domain 2 in complex with Trichostatin A (PDB ID: 5EDU). Through detailed in silico screening of the ZINC database, we shortlisted three hits as the lead molecules for designing novel HDAC6 inhibitors with better efficacy. Docking with 5EDU, followed by ADMET and TOPKAT analysis of modified ZINC hits provided 9 novel potential HDAC6 inhibitors that possess better docking scores and 2D interactions as compared to the control ZINC hit molecules. Finally, a 50 ns MD analysis run followed by Protein–Ligand Interaction Energy (PLIE) analysis of the top scored hits provided a novel molecule N1 that showed promisingly similar results to that of Ricolinostat (a known HDAC6 inhibitor). The comparable result of the designed hits to established HDAC6 inhibitors suggests that these compounds might prove to be successful HDAC6 inhibitors in future.

Graphical abstract

Designed novel hits that might act as good HDAC6 inhibitors derived from ZINC database using combined molecular docking and modeling approaches.

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Abbreviations

–CDIE:

–CDOCKER Interaction Energy

HDAC6i:

HDAC6 inhibitor

2D:

2 Dimensional

TSA:

Trichostatin A

Tub A:

Tubastatin A

ZBG:

Zinc Binding Group

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Acknowledgements

Priya Poonia would like to acknowledge ICMR for providing her SRF fellowship. Prakash Jha would like to thank the Department of Science and Technology, Government of India for awarding him DST-INSPIRE fellowship (Grant Number: DST/INSPIRE/03/2016/000026).

Funding

The authors would like to thank Dr. B.R. Ambedkar Center for Biomedical Research (ACBR), University of Delhi for providing the lab space and instrument facilities; DBT-BIC facility (BT/PR40153/137/8/2021) at ACBR from Department of Biotechnology, Government of India for providing software and hardware facility.

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  1. Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110036, India

    Priya Poonia, Monika Sharma, Prakash Jha & Madhu Chopra

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  1. Priya Poonia
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  2. Monika Sharma
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  3. Prakash Jha
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  4. Madhu Chopra
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Contributions

PP carried out the molecular docking and molecular modeling studies. MS carried out pharmacophore development and validation. MC conceived, designed, and coordinated the study. PJ carried out MD simulations, and compiled the methodology and results of the same. PP wrote the whole manuscript, and prepared the figures and tables. MC reviewed and commented on the manuscript.

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Correspondence to Madhu Chopra.

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11030_2022_10540_MOESM1_ESM.docx

Supplementary file1 Charts for training set and test set compounds used to build HDAC6 and HDAC1/2 pharmacophore. Result of pharmacophore validation and molecular docking results of ZINC hits (DOCX 2676 kb)

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Poonia, P., Sharma, M., Jha, P. et al. Pharmacophore-based virtual screening of ZINC database, molecular modeling and designing new derivatives as potential HDAC6 inhibitors. Mol Divers 27, 2053–2071 (2023). https://doi.org/10.1007/s11030-022-10540-3

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  • DOI: https://doi.org/10.1007/s11030-022-10540-3

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