Design of potential anti-melanoma agents against SK-MEL-5 cell line using QSAR modeling and molecular docking methods
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Design of potential anti‑melanoma agents against SK‑MEL‑5 cell line using QSAR modeling and molecular docking methods Abdullahi Bello Umar1 · Adamu Uzairu1 · Gideon Adamu Shallangwa1 · Sani Uba1 Received: 1 February 2020 / Accepted: 26 March 2020 © Springer Nature Switzerland AG 2020
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 p GI50 was recorded. The QSAR model was built using fifty (50) compounds and the best-generated model based on multiple linear regression showed, respectively 2 2 good quality of fits [ R2 (0.864), Radjusted (0.846), Q2cv (0.841) and Rpred (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 p GI50 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. Keywords SK-MEL-5 cell line · Melanoma · QSAR · Binding energy · π–π interaction · V600E-BRAF
1 Introduction SK-MEL-5 is a human melanoma cell line derived from a metastatic axillary node of a young female patient, and is characterized by a high level of expression of the V600E mutation of BRAF and the wild-type NRAS [1], as well as by relatively high levels of the ABCB1 transcript [2]. It has been used in various studies to explore new therapies against melanoma in various in vitro experiments [3, 4]. Several potent drugs are now available in clinical trials against melanoma including kinase inhibitors with different degree of success. Sorafenib one of the multikinase inhibitor, which inhibit EGFR tyrosine receptor
kinase, BRAF serine and threonine kinase [5]. vemurafenib (Zelboraf 1), a more distinct BRAF inhibitor was approved in 2011 by the FDA for melanoma (metastatic) [6]. However, Treatment with the use of BRAF inhibitors can result in the development of inhibitor (drug) resistance which restrict their usage [7]. Melanoma is a dangerous form of cancer that has a very bad
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