Structural insights into the mechanism of resistance to bicalutamide by the clinical mutations in androgen receptor in chemo-treatment resistant prostate cancer

Abstract

Despite advanced diagnosis and detection technologies, prostate cancer (PCa) is the most prevalent neoplasms in males. Dysregulation of the androgen receptor (AR) is centrally involved in the tumorigenesis of PCa cells. Acquisition of drug resistance due to modifications in AR leads to therapeutic failure and relapse in PCa. An overhaul of comprehensive catalogues of cancer-causing mutations and their juxta positioning on 3D protein can help in guiding the exploration of small drug molecules. Among several well-studied PCa-specific mutations, T877A, T877S and H874Y are the most common substitutions in the ligand-binding domain (LBD) of the AR. In this study, we combined structure as well as dynamics-based in silico approaches to infer the mechanistic effect of amino acid substitutions on the structural stability of LBD. Molecular dynamics simulations allowed us to unveil a possible drug resistance mechanism that acts through structural alteration and changes in the molecular motions of LBD. Our findings suggest that the resistance to bicalutamide is partially due to increased flexibility in the H₁₂ helix, which disturbs the compactness, thereby reducing the affinity for bicalutamide. In conclusion, the current study helps in understanding the structural changes caused by mutations and could assist in the drug development process.

Communicated by Ramaswamy H. Sarma

Keywords:

• Prostate cancer
• mutations
• drug resistance
• MD simulation
• PCA
• FEL

Acknowledgments

The author thank the Deanship of Scientific Research at Shaqra University for supporting this work.

Author contributions

Muhammad Tahir ul Qamar conceived and supervised this study. Abdul Majeed, Arooma Maryam and Muhammad Usman Mirza collected the data, performed experiments and write the first draft of the manuscript. Laila Alhussain, Seham Obaid Al Otaibi, Ahmad Almatroudi, Khaled S. Allemailem and Faris Alrumaihi validated the results and revised the manuscript. Muhammad Tahir ul Qamar, Abdulaziz A. Aloliqi and Faez Falah Alshehri arranged funding for this study and finalize the manuscript. All authors approved the final version.