Abstract:
Calcium (Ca2+) has been observed as the most important ion involved in a series of cellular
processes and its homeostasis is the most critical for normal cellular functions.
Mitochondrial Calcium Uniporter (MCU) complex has been recognized as the most
important calcium-specific channel located in the inner mitochondrial membrane,
responsible for Ca2+ homeostasis by transporting Ca2+ across the mitochondrial membrane.
Various reports suggest that any conformational defects in MCU result in increased Ca2+
uptake, leading to ROS mediated oxidative stress and positive regulation of MCU. ROS
production has been associated with oxidative stress leading to mitochondrial dysfunction
and thus, one of the major players in degenerative disorders such as neurodegeneration. To
overcome MCU-mediated oxidative stress several small molecules have been identified
through bioassays that modulate MCU activity. However, specificity, off-target toxicities,
and multidrug toxicities were identified as major limitations. Existing literature suggests
that MCU is a potential drug target for Ca2+ driven oxidative stress leading to various
degenerative disorders. Additionally, Due to the unavailability of in-silico studies, there
was no structural data available on known inhibitors with recently publish MCU crystal
structures. Within this article, we will perform dynamic simulations of static BRN to
validate MCU as a potential drug target. Furthermore, Structural modelling and dynamic
simulation of MCU pore-forming subunit was done using computational structural biology
approaches. Moreover, interaction profiling of organic and organometallic inhibitors and
their derivatives with MCU were studied before and after MD simulations to probe the
modulatory potential of both classes of known inhibitory data. Current study highlighted
that the hyperactivation of MCU along with Ca2+ concentration leads towards diseased
condition which can be revert to its normal condition by introducing an inhibitor within the
BRN. Furthermore, the residues present in DIME motif of MCU pore forming subunit
such as ASP261 and GLU264 are important residues for protein-ligand interactions. It was
also observed that electrostatic properties of ligand are not complementary to protein
binding site that results in lack of optimal fitness of the ligand. This further recommends
that more in-depth study and structural modeling of ligands are required.
