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

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 KLHL22 protein was predicted by the homology modelling. The model was evaluated by Ramanchandran 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 a 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 were 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.

Age-Related KLHL22 Expression in Human MSCs and Regenerative Implications

“…Recent studies have highlighted the importance of KLHL22 in disease and developmental processes. For instance, Gao (2023) demonstrated the potential of KLHL22 inhibitors in cancer therapy by targeting the mTORC1 pathway, which is also implicated in aging-related processes. Similarly, Zhou et al (2020) found that KLHL22 regulates PD-1 homeostasis on T cells, a mechanism that could influence age-related immune senescence.…”