Author(s):
1. Abdul Majeed:
Integrative Omics & Molecular Modeling Laboratory, Dept. of Bioinformatics and Biotechnology,
GCUF, Faisalabad, Pakistan.
2. Muhammad Tahir ul Qamar:
Integrative Omics & Molecular Modeling Laboratory, Dept. of Bioinformatics and Biotechnology,
GCUF, Faisalabad, Pakistan.
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.
Page(s):
151-151
DOI:
DOI not available
Published:
Journal: Abstract Book on International Conference on Food and Applied Sciences (ICFAS-23) 3-5 August 23, Volume: 0, Issue: 0, Year: 2023
Keywords:
PCA
,
Prostate cancer
,
Drug resistance
,
mutations
,
MD simulation
References:
References are not available for this document.
Citations
Citations are not available for this document.