Investigation of Hot Spot Region in XIAP Inhibitor Binding Site by Fragment Molecular Orbital Method
| Autor: | Ki Beom Shin, Hocheol Lim, Jongwan Kim, Ky Youb Nam, Jiwon Choi, Xuemei Jin, Kyoung Tai No, Sungbo Hwang |
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| Rok vydání: | 2019 |
| Předmět: |
Stereochemistry
lcsh:Biotechnology Biophysics Fragment molecular orbital method Inhibitor of apoptosis Biochemistry Natural product Protein–protein interaction 03 medical and health sciences chemistry.chemical_compound Protein-protein interaction 0302 clinical medicine Structural Biology lcsh:TP248.13-248.65 Neoeriocitrin XIAP-BIR3 inhibitor Genetics Binding site X-linked inhibitor of apoptosis protein 030304 developmental biology 0303 health sciences Tetrapeptide Drug discovery Chemistry MD simulation Computer Science Applications XIAP 030220 oncology & carcinogenesis Molecular docking Fragment molecular orbital Research Article Biotechnology |
| Zdroj: | Computational and Structural Biotechnology Journal Computational and Structural Biotechnology Journal, Vol 17, Iss, Pp 1217-1225 (2019) |
| ISSN: | 2001-0370 |
| DOI: | 10.1016/j.csbj.2019.08.004 |
| Popis: | X-linked inhibitor of apoptosis protein (XIAP) is an important regulator of cancer cell survival whose BIR3 domain (XIAP-BIR3) recognizes the Smac N-terminal tetrapeptide sequence (AVPI), making it an attractive protein-protein interaction (PPI) target for cancer therapies. We used the fragment molecular orbital (FMO) method to study the binding modes and affinities between XIAP-BIR3 and a series of its inhibitors (1–8) that mimic the AVPI binding motif; the inhibitors had common interactions with key residues in a hot spot region of XIAP-BIR3 (P1–P4 subpockets) with increased binding affinity mainly attributed to specific interactions with the P1 and P4 subpockets. Based on the structural information from FMO results, we proposed a novel XIAP natural product inhibitor, neoeriocitrin 10, which was derived from our preciously reported XIAP-BIR3 inhibitor 9, can be used as a highly potent candidate for XIAP-BIR3 inhibition. We also performed pair interaction energy decomposition analysis to investigate the binding energies between specific binding residues and individual ligands, showing that the novel natural product neoeriocitrin 10 had a higher binding affinity than epicatechin gallate 9. Molecular docking and dynamics simulations were performed to explore the mode of binding between 10 and XIAP-BIR3, demonstrating that 10 binds more strongly to the P1 and P4 pockets than 9. Overall, we present a novel natural product, neoeriocitrin 10, and demonstrate that the FMO method can be used to identify hot spots in PPIs and design new compounds for XIAP inhibition. Graphical Abstract Unlabelled Image |
| Databáze: | OpenAIRE |
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