Abstract

Lung cancer ranks number one among the all cancer types in the world, out of which 85% are non-small cell lung cancer (NSCLC). In case of NSCLC, a substitution mutation of Leu 858 Arg (L858R) in the gene of Epidermal Growth Factor Receptor (EGFR) has been reported. Hence, targeting EGFR containing L858R mutation using inhibitors is well reported strategy to discover potential drugs against NSCLC. The present work aims to identify the potent inhibitors against EGFR L858R from Vernonia cinerea plant. A library of 45 phytochemicals was subjected to virtual screening using rigid and flexible docking. 12 potential phytochemicals were screened by molecular docking with high binding energy (between -8.0 and -9.7 kcal mol⁻¹). Two compounds viz., luteolin -7-glucoside and epicatechin gallate showed interaction with Met793 of EGFR-L858R which was similar to the reference inhibitor PD168393. To analyze the stability of the luteolin -7-glucoside and epicatechin gallate with EGFR L858R, molecular dynamics simulations were conducted in explicit water conditions using 60 nanosecond. The results of hydrogen bonding patterns, radius of gyration, deviations in conformational elements, fluctuations in the residual components, and solvent accessible surface area revealed better stability of luteolin -7-glucoside and epicatechin gallate with EGFR-L858R as compared to PD168393. Therefore, we conclude that luteolin -7-glucoside and epicatechin gallate have excellent inhibition properties thus they can be used further to develop effective drugs against lung cancer having EGFR-L858R mutation.

Communicated by Ramaswamy H. Sarma

摘要

肺癌在全球所有癌症类型中排名第一，其中85%为非小细胞肺癌（NSCLC）。在非小细胞肺癌的情况下，已经报道了表皮生长因子受体 (EGFR) 基因中 Leu 858 Arg (L858R) 的替代突变。因此，使用抑制剂靶向含有 L858R 突变的 EGFR 是发现针对 NSCLC 的潜在药物的策略。目前的工作旨在从斑鸠菊属植物中鉴定针对 EGFR L858R 的强效抑制剂。使用刚性和柔性对接对包含 45 种植物化学物质的库进行虚拟筛选。通过具有高结合能（-8.0 至 -9.7 kcal mol ^-1）。两种化合物，即木犀草素-7-葡萄糖苷和表儿茶素没食子酸酯显示出与 EGFR-L858R 的 Met793 的相互作用，这与参考抑制剂 PD168393 相似。为了分析木犀草素-7-葡萄糖苷和表儿茶素没食子酸酯与 EGFR L858R 的稳定性，在明确的水条件下使用 60 纳秒进行了分子动力学模拟。氢键模式、回转半径、构象元素的偏差、残留成分的波动和溶剂可及表面积的结果表明，与 PD168393 相比，木犀草素 -7-葡萄糖苷和表儿茶素没食子酸酯与 EGFR-L858R 具有更好的稳定性。所以，

由 Ramaswamy H. Sarma 交流