Microsecond Simulation of the Proteoglycan-like Region of Carbonic Anhydrase IX and Design of Chemical Inhibitors Targeting pH Homeostasis in Cancer Cells

ACS Omega
Arun JohnSulochana Konerirajapuram Natarajan

Abstract

Carbonic anhydrase IX (CAIX) is a membrane-bound enzyme associated with tumor hypoxia and found to be over expressed in various tumor conditions. Targeting CAIX catalytic activity is proven to be efficient modality in modulating pH homeostasis in cancer cells. Proteoglycan-like (PG) region is unique to CAIX and is proposed to serve as an antenna enhancing the export of protons in conjunction with facilitated efflux of lactate ions via monocarboxylate transporters. Moreover, the PG region is also reported to contribute to the assembly and maturation of focal adhesion links during cellular attachment and dispersion on solid supports. Thus, drug targeting of this region shall efficiently modulate pH homeostasis and cell adhesion in cancer cells. As the PG region is intrinsically disordered, the complete crystal structure is not elucidated. Hence, in this study, we intend to sample the conformational landscape of the PG region at microsecond scale simulation in order to sample the most probable conformations that shall be utilized for structure-based drug design. In addition, the sampled conformations were subjected to high-throughput virtual screening against NCI and Maybridge datasets to identify potential hits based on consensus...Continue Reading

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Citations

May 14, 2020·Journal of Biomolecular Structure & Dynamics·Vijay Kumar BhardwajSanjay Kumar
May 26, 2020·Journal of Biomolecular Structure & Dynamics·Vijay Kumar Bhardwaj, Rituraj Purohit
Nov 18, 2020·Cellular and Molecular Life Sciences : CMLS·Emma LangellaSimona Maria Monti

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Methods Mentioned

BETA
X-ray
phage display
PCA
Assay

Software Mentioned

FAST
Kpax
ModRefiner
WHATCHECK
NIH Image J
Gromacs
FG
XMGRACE
MD
FEL

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