Computational structure–activity study directs synthesis of novel antitumor enkephalin analogs

Abstract

The capability of a Support Vector Machines QSAR model to predict the antiproliferative ability of small peptides was evaluated by screening a virtual library of enkephalin-like analogs modified by incorporation of the (R,S)-(1-adamantyl)glycine (Aaa) residue. From an initial set of 390 compounds, the peptides, Tyr-Aaa-Gly-Phe-Met (2), Tyr-Aaa-Gly-Phe-Phe (3), Phe-Aaa-Gly-Phe-Phe (4) and Phe-Aaa-Gly-Phe-Met (5) were selected, synthesized and their antitumor activity was tested and compared to that of Met-enkephalin (1). The antiproliferative activity correlated with the computational prediction and with the foldamer-forming ability of the studied peptides. The most active compounds were the hydrophobic peptides, Phe-Aaa-Gly-Phe-Phe (4) and Phe-Aaa-Gly-Phe-Met (5), having a greater propensity to adopt folded structures than the other peptides.

Predicting Antitumor Activity of Peptides by Consensus of Regression Models Trained on a Small Data Sample

“…Rankings of first 10 compounds in each of four lists were combined using the majority voting and yielded a final list where the first position has been reached with the minimal score. The final list of first 15 compounds is presented in Table 1 together with the top 10 compounds predicted by [12]; compound 10 had an overall score equal to 4 implying that it was first on the list of each of four regression models. The first 5 compounds were in the top 10 compounds in each of the four lists.…”

“…It was found that the replacement of Gly 2 with ( R,S )-(1-adamantyl)glycine (Ada) gave the most effective derivative with antitumor activity against HEp-2, HBL, SW-620 and Caco-2 cell lines in vitro . Afterwards, the support vector machines (SVM) QSAR approach was undertaken to screen a virtual library of OGF-related compounds and identify novel structures with possibly improved antitumor activities [12]. Some of the top-rated compounds obtained by computational prediction were synthesized and showed more pronounced activity on the selected cancer cell lines.…”

“…The highly ranked candidate compounds were synthesized, characterized and tested for an antiproliferative activity. The activities were compared against compounds selected previously from the same virtual library by the radial basis function SVM regression model [12]. …”

Inhibition of the growth of human melanoma cells by methionine enkephalin

“…These receptors are expressed on the surface of immune cells and various tumor cells, including pancreatic cancer and melanoma cells (13,14). MENK upregulates the activity of immune cells and may inhibit tumor growth (15,16). MENK and opioid receptors form a biological axis that regulates cell proliferation by delaying G1/S cell cycle progression under homeostatic conditions and in neoplasia, and inhibits pancreatic tumor progression (17).…”

Methionine enkephalin (MENK) improves lymphocyte subpopulations in human peripheral blood of 50 cancer patients by inhibiting regulatory T cells (Tregs)

“…[6][7][8][9][10][11][12] In addition, there have been studies indicating that MENK could inhibit tumor growth. 13,14 However, so far there is little approach to the influence on lymphocyte subpopulations in large samples of cancer patients by MENK. Due to the importance of sustaining immunity in cancer patients and based on the data we have had on MENK we MeNK, a penta-peptide is considered as being involved in the regulatory feedback loop between the immune and neuroendocrine systems, with marked modulation of various functions of human immune cells.…”