Heliyon (Sep 2019)
Extracellular binding of indinavir to matrix metalloproteinase-2 and the alpha-7-nicotinic acetylcholine receptor: implications for use in cancer treatment
Abstract
Introduction: Results from recent studies have suggested a role for protease inhibitors in altering mechanisms involved in the initiation and proliferation of cancer cells. One such inhibitor, indinavir, may act as an anti-cancer agent by modulating the alpha-7-nicotinic acetylcholine receptor, which is a pro-carcinogenic protein that has been researched in conjunction with nicotine in lung cancer development. In our study, we compare indinavir's binding affinity towards α7-nAchR and MMP-2, another promoter of malignancy, to determine what extracellular effects the drug has before being internalized to inhibit HIV-1 protease. Methods: A computer program, PyRx, was used to compare indinavir's binding affinity with digital models for α7-nAchR, MMP-2 and HIV-1 protease, which were then compared to the results of in vitro binding assays for these targets. Results: PyRx testing predicted the highest binding affinity values for indinavir to MMP-2 (mean = 8.77 kcal/mol, S.D. = 0.29), followed by the α7-nAchR (mean = 8.53 kcal/mol, S.D. = 0.15) and HIV-1 protease (mean = 7.5 kcal/mol, S.D. = 0.44). In vitro, indinavir's mean percent inhibition of control values were 103.2 for HIV-1 protease, 5.3 for MMP-2, and 7.7 for the α7-nAchR. Conclusions: Binding affinity values for indinavir to MMP-2 and α7-nAchR were not significantly different. Using PyRx to predict affinity compared with in vitro testing did not yield comparable results. However, indinavir was shown to slightly inhibit both α7-nAchR and MMP-2, which may have ramifications in the drug's delivery to the intracellularly located HIV-1 protease.
