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All Journal Journal of Tropical Life Science : International Journal of Theoretical, Experimental, and Applied Life Sciences
Husain, Syarifuddin
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Agriculture, Biological Sciences & Forestry Environmental Science

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Rational Design of Peptide Inhibitor Targeting BRCA1-Associated Protein 1 Through Homology Modeling and Molecular Dynamics Simulation: Rational Design of BRCA1-Associated Protein 1 Peptide Inhibitor Husain, Syarifuddin; Mohamed, Ruzianisra; Abd Halim, Khairul Bariyyah; Mohd Mutalip, Siti Syairah; Hairuddin, Omar Nafiis
Journal of Tropical Life Science Vol. 15 No. 2
Publisher : Journal of Tropical Life Science

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.11594/jtls.15.02.12

Abstract

Cancer remains a complex and heterogeneous disease, with the BRCA1-Associated Protein 1 (BAP1) recognized as a tumour suppressor gene playing a vital role in various cellular processes. Interestingly, BAP1 is overexpressed in certain cancers, and inhibition of its ubiquitin C-terminal hydrolase (UCH) domain may offer a promising therapeutic strategy. This study aims to identify the key residues involved in the interaction between ubiquitin and BAP1 and to design peptide inhibitors capable of selectively targeting BAP1’s deubiquitinating activity. A 3D protein model of the BAP1–ubiquitin complex was generated using AlphaFold, followed by molecular dynamics (MD) simulations to identify critical interacting residues. Peptide inhibitors were designed based on the β-turn region of ubiquitin, and molecular docking was performed using the HADDOCK 2.4 server. Based on the result, it was observed that mutating Lys6 and Thr9 to arginine improved binding affinity between the cyclic peptide inhibitors and the BAP1, probably due to the complementary attraction between the positively charged arginine residue and the negatively charged surface electrostatic potential of the BAP1 distal site. MD simulations were conducted to assess the stability and interactions of the BAP1-peptide complexes, showing that the CP3K6R/T9R mutant exhibited the highest average number of hydrogen bonds and the strongest binding affinity. The study suggests that electrostatic interactions and residue-specific mutations can be used to optimise peptide inhibitors for BAP1. The findings support the possibility of developing therapeutic strategies to inhibit BAP1 and suppress tumour progression.
BRCA1-Associated Protein 1 and Its Role of Cell Cycle Regulation in Cancer: BRCA1-Associated Protein 1 In Cell Cycle Regulation Husain, Syarifuddin; Mohamed, Ruzianisra; Abd Halim, Khairul Bariyyah; Mohd Mutalip, Siti Syairah
Journal of Tropical Life Science Vol. 16 No. 01 (2026)
Publisher : Journal of Tropical Life Science

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.11594/16.01.01

Abstract

BRCA1-associated protein 1 (BAP1) plays a critical role in regulating the cell cycle, exhibiting both tumor-suppressive and oncogenic roles. It controls the expression and stability of key cell cycle regulators, including cyclin D1, p27, and Krüppel-like factor 5 (KLF5), ensuring proper progression through the G1–S checkpoint. Dysregulation of these processes due to altered BAP1 activity can promote uncontrolled proliferation and contribute to tumor progression. This review focuses on the dual roles of BAP1 in cell cycle regulation and highlights how its functional impairment creates vulnerabilities that can be therapeutically exploited. Cyclin D1 is discussed as a potential target to mitigate cell cycle dysregulation driven by BAP1. By emphasizing the molecular mechanisms underlying BAP1 influence on transcriptional programs and protein stability, this work provides insights into strategies for managing malignancies associated with altered BAP1 activity. Mechanistic studies indicate that BAP1 exerts tumor-suppressive effects by interacting with Host Cell Factor-1, Breast Cancer Type 1 Susceptibility protein/BRCA1-Associated RING Domain 1, and KLF5 to maintain proper cell cycle progression. Conversely, BAP1 can exert oncogenic roles in certain cancers by stabilizing KLF5, enhancing cyclin D1 expression, and suppressing p27, thereby promoting proliferation through the Phosphoinositide 3-Kinase/Protein Kinase B/Mechanistic Target of Rapamycin and E2F/Retinoblastoma pathways. These findings underscore cyclin D1 as a convergent node of BAP1-mediated regulation, highlighting its potential as a therapeutic target to restore cell cycle control in malignancies driven by BAP1 dysfunction.
Co-Authors Abd Halim, Khairul Bariyyah Hairuddin, Omar Nafiis Mohamed, Ruzianisra Mohd Mutalip, Siti Syairah