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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Design and Screening of KLHL22 Inhibitors by Homology Modeling, Molecular Docking, and Molecular Dynamics Simulation

Author(s): Chenglong Gao, Chuance Sun, Lichuan Zhang, Haoran Zhang, Rilei Yu and Congmin Kang*

Volume 20, Issue 3, 2023

Published on: 30 June, 2022

Page: [291 - 303] Pages: 13

DOI: 10.2174/1570180819666220422101618

Price: $65

Abstract

Background: Kelch-like protein 22 (KLHL22) was a newly discovered proto-oncogene and it is highly expressed in multiple breast cancer cell lines. Inhibition of KLHL22 can induce autophagy in tumor cells by regulating the mTORC1 pathway.

Methods: In this study, the structure of the KLHL22 protein was predicted by homology modelling. The model was evaluated by Ramachandran Plot and Profile-3D. Virtual screening of a drug-like small molecule library of 400,000 compounds was performed, and six potentially active compounds were obtained.

Results: Among them, compound 1 had the best docking posture with docking energy of -8.42 kcal/mol. Therefore, we further modified the structure of compound 1. 12 unreported compounds with lower docking energies were obtained. The results of ADMET prediction performed on them showed good druggability. The 60 ns molecular dynamics simulations were performed for compounds 1 and 10. MD studies showed that the complexes had stable RMSD, and the compounds formed good H-bonds interactions with essential amino acids (ASP64, TRP192).

Conclusion: These results may provide new insights into the design and development of potent novel KLHL22 inhibitors.

Keywords: Homology modeling, virtual screening, molecular docking, dynamics simulation, ADME, structure modification

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