| Summary: | Statins are commonly prescribed in the management of cardiovascular diseases;
however, they can lead to statin-associated muscle symptoms (SAMS), which are often
related to mitochondrial dysfunction. Monocarboxylate transporter (MCT1) is a
proton-linked monocarboxylate transporter that facilitates the cellular uptake of
statins, influencing their pharmacokinetics and potential effects on cellular metabolism
and mitochondrial function. Although direct interactions between statins and MCT1
are not well-documented, emerging evidence suggests that mitochondrial dysfunction
associated with statins may involve MCT1-mediated mechanisms, potentially through
alterations in lactate transport and metabolic regulation.. This study explores the
molecular interactions between statins and MCT1, focusing on their binding affinities
and the subsequent effects on mitochondrial function and gene regulation. The 3D
structure of MCT1 from Rattus norvegicus was modeled using the Swiss-Model
database, based on similar sequences from Mus musculus. Molecular docking
analyses, employing both blind and specific docking methods, indicated that
atorvastatin lactone had the highest binding affinity to MCT1 (-8.7 kcal/mol and -9.2
kcal/mol, respectively), followed by rosuvastatin lactone (-7.5 kcal/mol and -7.9
kcal/mol), simvastatin lactone (-7.7 kcal/mol for both), pravastatin lactone (-7.4
kcal/mol for both), and simvastatin acid (-5.7 kcal/mol and -6.0 kcal/mol). Of all
statins analyzed, simvastatin acid does not have any hydrogen bonds with amino acid
residues of MCT1 thus could explained its lowest binding affinity. It unlike other statins. Important binding residues, including LEU132, TYR70, and THR388, were
identified as essential for ligand interactions. By identifying the key molecular
interactions that contribute to SAMS, this study establishes a solid framework for early
prediction of MCT1 involvement during the pathology process
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