Design of potential anti-melanoma agents against SK-MEL-5 cell line using QSAR modeling and molecular docking methods

Abstract

SK-MEL-5 is a human melanoma cell line that has been used in several researches to explore new therapies against melanoma. Based on this study we report on the development of quantitative structure–activity relationship (QSAR) model and molecular docking simulation able to predict the cytotoxic effect of diverse chemical compounds on this cancer cell line. The dataset of seventy-two (72) cytotoxic compounds were downloaded from the National Cancer Institute database. It contains the data of compounds for which cytotoxicity results expressed by pGI50 was recorded. The QSAR model was built using fifty (50) compounds and the best-generated model based on multiple linear regression showed, respectively good quality of fits [ $$R^{2}$$ (0.864), $$R_{adjusted}^{2}$$ (0.846), Q2cv (0.841) and $$R_{pred}^{2}$$ (0.885)]. The model’s predictive ability was determined by a test set of twenty-two (22) compounds and the applicability domain was assessed through leveraged approach. Compounds 41 and 69 were selected as templates for in silico design because they had high pGI50 activity and are within the model’s applicability domain. The obtained information from the model was explored to design novel compounds by introducing various substituents. Moreover, the designed compounds were docked into the active site of the protein (PDB CODE: 3OG7) which is responsible for melanoma cancer to elucidate their binding mode. Ia (− 12.4 kcal mol−1) and IIb (− 12.3 kcal mol−1) showed a better binding affinity for the target when compared with (vemurafenib, − 11.3 kcal mol−1) the known inhibitor of the target (V600E-BRAF). These results may be of great help in early anticancer drug discovery.