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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

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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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[1]
Alsayed, A.; Alshamsan, B.; Elhassan, T.; Ajarim, D.; Badran, A.; Elshenawy, M.; Suleman, K. Metaplastic breast cancer: Disease characteristics and outcome in Arab women. J. Clin. Oncol., 2021, 39(15)(Suppl.), 39.
[http://dx.doi.org/10.1200/JCO.2021.39.15_suppl.e12534]
[2]
Dibble, C.C.; Manning, B.D. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat. Cell Biol., 2013, 15(6), 555-564.
[http://dx.doi.org/10.1038/ncb2763] [PMID: 23728461]
[3]
Laplante, M.; Sabatini, D.M. mTOR signaling in growth control and disease. Cell, 2012, 149(2), 274-293.
[http://dx.doi.org/10.1016/j.cell.2012.03.017] [PMID: 22500797]
[4]
Yuan, H-X.; Xiong, Y.; Guan, K-L. Nutrient sensing, metabolism, and cell growth control. Mol. Cell, 2013, 49(3), 379-387.
[http://dx.doi.org/10.1016/j.molcel.2013.01.019] [PMID: 23395268]
[5]
Efeyan, A.; Sabatini, D.M. MTOR: From growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol., 2011, 12(1), 21-35.
[6]
Kim, E.; Goraksha-Hicks, P.; Li, L.; Neufeld, T.P.; Guan, K-L. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol., 2008, 10(8), 935-945.
[http://dx.doi.org/10.1038/ncb1753] [PMID: 18604198]
[7]
Sancak, Y.; Peterson, T.R.; Shaul, Y.D.; Lindquist, R.A.; Thoreen, C.C.; Bar-Peled, L.; Sabatini, D.M. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science, 2008, 320(5882), 1496-1501.
[http://dx.doi.org/10.1126/science.1157535] [PMID: 18497260]
[8]
Bar-Peled, L.; Chantranupong, L.; Cherniack, A.D.; Chen, W.W.; Ottina, K.A.; Grabiner, B.C.; Spear, E.D.; Carter, S.L.; Meyerson, M.; Sabatini, D.M. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science, 2013, 340(6136), 1100-1106.
[http://dx.doi.org/10.1126/science.1232044] [PMID: 23723238]
[9]
Chen, J.; Ou, Y.; Yang, Y.; Li, W.; Xu, Y.; Xie, Y.; Liu, Y. KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing. Nature, 2018, 557(7706), 585-589.
[http://dx.doi.org/10.1038/s41586-018-0128-9] [PMID: 29769719]
[10]
Muhammed, M.T.; Aki-Yalcin, E.; Gohil, N. Homology modeling in drug discovery: Overview, current applications, and future perspectives. Chem. Biol. Drug Des., 2019, 93(1), 12-20.
[http://dx.doi.org/10.1111/cbdd.13388] [PMID: 30187647]
[11]
Skone, G.; Cameron, S. Protein Structure Computation. Frontiers in the Convergence, IEEE,, 2007, 135-140.
[http://dx.doi.org/10.1109/FBIT.2007.96]
[12]
Cai, C.; Wu, Q.; Luo, Y.; Ma, H.; Shen, J.; Zhang, Y.; Yang, L.; Chen, Y.; Wen, Z.; Wang, Q. In silico prediction of ROCK II inhibitors by different classification approaches. Mol. Divers., 2017, 21(4), 791-807.
[http://dx.doi.org/10.1007/s11030-017-9772-5] [PMID: 28770474]
[13]
Kheder, N.A. Hydrazonoyl chlorides as precursors for synthesis of novel bis-pyrrole derivatives. Molecules, 2016, 21(3), 326.
[http://dx.doi.org/10.3390/molecules21030326] [PMID: 27005604]
[14]
Wang, C-X.; Chang, S.; Gong, X.; Yang, F.; Li, C-H.; Chen, W-Z. Progress in the scoring functions of protein-protein docking. Wuli Huaxue Xuebao, 2012, 28(4), 751-758.
[http://dx.doi.org/10.3866/PKU.WHXB201202022]
[15]
Hess, B.; Kutzner, C.; van der Spoel, D.; Lindahl, E. GROMACS 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation. J. Chem. Theory Comput., 2008, 4(3), 4.
[http://dx.doi.org/10.1021/ct700301q]
[16]
Stocker, U.; van Gunsteren, W.F. Molecular dynamics simulation of hen egg white lysozyme: A test of the GROMOS96 force field against nuclear magnetic resonance data. Proteins, 2000, 40(1), 145-153.
[http://dx.doi.org/10.1002/(SICI)1097-0134(20000701)40:1<145:AID-PROT160>3.0.CO;2-Y] [PMID: 10813839]
[17]
Schüttelkopf, A.W.; van Aalten, D.M. PRODRG: A tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr. D Biol. Crystallogr., 2004, 60(Pt 8), 1355-1363.
[http://dx.doi.org/10.1107/S0907444904011679] [PMID: 15272157]
[18]
Yang, Z.R.; Chou, K-C. Bio-support vector machines for computational proteomics. Bioinformatics, 2004, 20(5), 735-741.
[http://dx.doi.org/10.1093/bioinformatics/btg477] [PMID: 14751989]

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