Abstract
ND1 subunit possesses the majority of the inhibitor binding domain of the human mitochondrial respiratory complex I. This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, that some metabolites from Annona muricata called acetogenins have important biological activities, such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine mitochondrial respiratory complex I by bis-tetrahydrofurans acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human mitochondrial respiratory complex I. In this work, we evaluate the in silico molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, quantum mechanical optimizations, molecular dynamics simulations and the molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known mitochondrial respiratory complex I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger binding free energy compared to the rotenone complex. Detailed analysis of the binding free energy shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of the mitochondrial respiratory complex I.
Highlights
It has been almost 100 years since Warburg presented the first connection between the mitochondria and tumors appearance [1]
In order to ensure the convergence of our mechanics/Poisson–Boltzmann surface area (MM/PBSA) results, we have considered only the last stable 200 ns (20 frames) of the molecular dynamics (MD) trajectories and were assessed using the Free Energy Landscape (FEL) analyses from each complex
The ND1 subunit has a predominantly structural conformation of alphahelices that provides the hydrophobic environment expected of a membrane protein and owns the quinone binding domain which is in its core (Table 1)
Summary
It has been almost 100 years since Warburg presented the first connection between the mitochondria and tumors appearance [1]. The mitochondria fulfill an energetic role in cells, in cancer cells; this role is essential for developing tumors through glycolysis [2,3]. The mitochondrial respiratory complex I (MRC-I) is directly involved in the appearance of colorectal cancer [9], prostate cancer [10], endometrial cancer [11], breast cancer [12], and melanoma [13]. This complex protein has become a therapeutic target to develop anticancer drugs. The MRC-I catalyze the formation of reactive oxygen species (ROS)
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