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

Author:

Kang Congmin1,Gao Chenglong1,Sun Chuance1,Zhang Lichuan1,Zhang Haoran1,Yu Rilei2

Affiliation:

1. College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China

2. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China

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.

Funder

National Natural Science Foundation of China

Publisher

Bentham Science Publishers Ltd.

Subject

Drug Discovery,Pharmaceutical Science,Molecular Medicine

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