Modulation of Calcium Activated Chloride Channel, TransMembrane 16 A (Tmem16A) in Glioblastoma Multiforme

Abstract

Glioblastoma, a lethal form of brain cancer, poses a significant challenge in the field of oncology due to its aggressive nature and limited treatment options. The transmembrane protein TMEM16A, also known as CaCC (Calcium-activated chloride channel), has emerged as a potential therapeutic target for its involvement in tumorigenic processes and its dysregulation in glioblastoma. This study investigated the modulation of TMEM16A in glioblastoma and explored its potential as a drug target. To understand the complex regulatory mechanisms governing TMEM16A's role in glioblastoma, a knowledge based BRN of TMEM16A and other relevant molecular players implicated in glioblastoma progression was constructed. This knowledge-driven BRN provided a systems-level understanding of the intricate interactions and signaling pathways contributing to the aberrant behavior of glioblastoma cells. Subsequently, dynamic simulations of the network were performed using Boolean logic parameters to analyze the dynamic behavior of the regulatory network under normal and pathophysiological conditions. These simulations facilitated the identification of key regulatory nodes and potential therapeutic targets, including TMEM16A, for glioblastoma treatment. By simulating the response of the BRN to different perturbations and concentrations, the network's stability and potential vulnerabilities were evaluated for therapeutic interventions. Furthermore, molecular dynamic simulations of Tmem16A were performed to probe the structural stability of Tmem16A and its ligand bound complexes. The current study highlighted that hyper-activation of TMEM16A is associated with diseased conditions, which could be maintained to its normal state by introducing an inhibitor in the BRN. Furthermore, protein ligand interaction profiling of Tmem16A with four shortlisted inhibitors of this channel i.e. CaCC(inh)A01, MONNA, Niclosamide, & NPPB depicted that a residue ARG788, present in the binding pocket located in the neck region of this protein might be important for the interaction between Tmem16A and these ligands. Also two residues, LYS839 & PRO365 might be crucial for achieving activity or potency against Tmem16A. It is also possible that the inhibitors of this channel might share an overlapping binding site. Overall, this study unveils the role of TMEM16A in glioblastoma, showing ways to potential therapeutic interventions against Glioblastoma Multiforme.