Extracellular binding of indinavir to matrix metalloproteinase-2 and the alpha-7-nicotinic acetylcholine receptor: implications for use in cancer treatment

Abstract

IntroductionResults 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.MethodsA 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.ResultsPyRx 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.ConclusionsBinding 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.

Repurposing of Antimicrobial Agents for Cancer Therapy: What Do We Know?

“…Usually, Indinavir is prescribed to patients as a retro-viral combination treatment (e.g., with Ritonavir) to avoid resistance development [135][136][137][138]. In a programmed computer model, Indinavir has been found to modulate the alpha-7 nicotinic acetylcholine receptor (a pro-carcinogenic protein) and the matrix metalloproteinase-2 (MMP-2), a malignancy promotor [139]. In HPV-induced cervical cancer cells, Indinavir reduces cell viability, decreases the secretion of MMP-2 and MMP-9, and induces apoptosis.…”

Targeting Alpha7 Nicotinic Acetylcholine Receptors in Lung Cancer: Insights, Challenges, and Therapeutic Strategies

“…However, the effect of this compound on cancer remains to be proven because it can act on α7 nAChR, MMP-2, and MMP-9, which are correlated with cancer metastasis. 109 Some synthetic chemical ligands acting as α7 nAChR antagonists have been derived from the simplified structure of naturally derived ligands. A ring E analogue and a ring AEbicyclic analogue of MLA were synthesized and modified in terms of ester and nitrogen side-chain.…”

“…Indinavir, which is an antiviral drug acting as a protease inhibitor, acts as a α7 nAChR antagonist at concentrations of >10 μM, whereas it functions as a positive allosteric modulator at concentrations of <10 μM. However, the effect of this compound on cancer remains to be proven because it can act on α7 nAChR, MMP-2, and MMP-9, which are correlated with cancer metastasis …”