Abstract

Autophagy and apoptosis are the two crucial processes of programmed cell death found in all eukaryotic cells; however, the elevated physiological stress in the tumor microenvironment leads to uncontrolled up-regulation in the process of autophagy. Available literatures suggest that inhibiting up-regulated autophagy in the cancerous cells may lead to the apoptosis and thereby culminate to tumor clearance. Several studies have been performed to design autophagy-inhibitors using either Beclin-1 or Bcl-2 as a target in isolation. However, to overcome the constraints of the availability of small and potent autophagy inhibitors, we have attempted extensive computational approach of repurposing the FDA-approved drugs from the ZINC database in order to inhibit the interaction between the Beclin1 and Bcl-2. Out of 1565 FDA-approved drugs used in our computational work, we sorted the drugs Ponatinib, Simeprevir, and Nilotinib through various methods viz. molecular docking, Lipinski’s filter, MD simulation and MM/PBSA, and we found these aforementioned drugs to show good binding energy and favorable interaction with the BH3 domain of Beclin1. We anticipate from our computational results that these drugs may become potent candidates to inhibit autophagy and exhibit the apoptosis in the tumor microenvironment and combat the current limitation of potent autophagy inhibitors; however, to substantiate our in-silico results, further experimental validations of these drug molecules are currently in progress.

Communicated by Ramaswamy H. Sarma

摘要

自噬和细胞凋亡是在所有真核细胞中发现的程序性细胞死亡的两个关键过程。然而，肿瘤微环境中升高的生理压力导致自噬过程中不受控制的上调。现有文献表明，抑制癌细胞中上调的自噬可能导致细胞凋亡，从而最终清除肿瘤。已经进行了几项研究以单独使用 Beclin-1 或 Bcl-2 作为靶标来设计自噬抑制剂。然而，为了克服小而有效的自噬抑制剂可用性的限制，我们尝试了广泛的计算方法，从 ZINC 数据库中重新利用 FDA 批准的药物，以抑制 Beclin1 和 Bcl-2 之间的相互作用。在我们的计算工作中使用的 1565 种 FDA 批准的药物中，我们通过各种方法对药物 Ponatinib、Simeprevir 和 Nilotinib 进行了分类。分子对接、Lipinski 滤波器、MD 模拟和 MM/PBSA，我们发现上述药物显示出良好的结合能和与 Beclin1 的 BH3 结构域的良好相互作用。我们从计算结果中预计，这些药物可能成为抑制自噬并在肿瘤微环境中表现出细胞凋亡并对抗当前有效自噬抑制剂限制的有效候选药物；然而，为了证实我们的 我们发现这些上述药物显示出良好的结合能和与 Beclin1 的 BH3 结构域的良好相互作用。我们从计算结果中预计，这些药物可能成为抑制自噬并在肿瘤微环境中表现出细胞凋亡并对抗当前有效自噬抑制剂限制的有效候选药物；然而，为了证实我们的 我们发现这些上述药物显示出良好的结合能和与 Beclin1 的 BH3 结构域的良好相互作用。我们从计算结果中预计，这些药物可能成为抑制自噬并在肿瘤微环境中表现出细胞凋亡并对抗当前有效自噬抑制剂限制的有效候选药物；然而，为了证实我们的在计算机模拟结果中，这些药物分子的进一步实验验证目前正在进行中。

由 Ramaswamy H. Sarma 传达