Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai 600 006, Tamil Nadu, India.
Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai 600 006, Tamil Nadu, India; National Institute of Traditional Medicine, Indian Council of Medical Research, Department of Health Research (Govt. of India), Belagavi 590010, India.
Life Sci. 2021 Mar 15;269:119082. doi: 10.1016/j.lfs.2021.119082. Epub 2021 Jan 19.
Glaucoma is the second leading cause of blindness in the world and is characterized by the loss of retinal ganglion cells (RGC) over a period of time, leading to complete blindness. Recently, endothelin has been identified as an important factor that influences intraocular pressure IOP, OBF, and direct RGC damage. Targeting the endothelin receptor signaling pathway in glaucoma is considered to be highly beneficial, as it can effectively modulate IOP, OBF, and RGC damage, the key factors which are essential to modulate the disease progression holistically. Currently, synthetic drugs like Bosentan, BQ-123, and prostaglandin analogues are available as endothelin receptor antagonists, which are extensively used in the treatment of cardiovascular and other conditions like systemic hypertension. However, the usage of these drugs in glaucoma is limited due to toxicity and poor bioavailability in the ocular milieu. Thus, there is a need for potential natural compounds as endothelin receptor antagonists that acts as dual inhibitors by targeting both ETA and ETB and are highly efficient with the least toxicity. Hence, this study is intended to prioritize endothelin receptor antagonists by structural bioinformatics approaches involving molecular modeling, molecular dynamics, and molecular docking studies. Subsequently, High throughput virtual screening (HTVS) vs. Natural compound databases targeting the optimal binding sites of both ETA and ETB. Following this, the common hits were subjected to binding free energy calculations (MMGBSA) and ADMETox analysis. Finally, the most potential hits were analyzed for MD based binding stability analysis and binding free energy. Similarly, the known synthetic inhibitors were also docked to the receptors and the results were analyzed. From this study, it was inferred that among the natural compounds dataset (8929 compounds), only 4 common compounds were identified as hits. Among these, only one compound ST075640 surpassed all the prioritization criteria including MMGBSA, ADMETox prediction, dual inhibitory potential (ETA & ETB), and also in structural comparative analysis with bosentan it showed similar efficiency. Thus, the validated hit shall prove to be effective in modulating endothelin mediated IOP, OBF, and RGC damage in glaucomatous condition.
青光眼是世界上第二大致盲原因，其特征是视网膜神经节细胞 (RGC) 在一段时间内逐渐丧失，最终导致完全失明。最近，内皮素已被确定为影响眼内压 (IOP)、OBF 和直接 RGC 损伤的重要因素。靶向青光眼内皮素受体信号通路被认为具有高度益处，因为它可以有效地调节 IOP、OBF 和 RGC 损伤，这些是全面调节疾病进展的关键因素。目前，博来霉素、BQ-123 和前列腺素类似物等合成药物可用作内皮素受体拮抗剂，广泛用于心血管疾病和其他疾病如系统性高血压的治疗。然而，由于这些药物在眼部环境中的毒性和生物利用度差，因此在青光眼治疗中的使用受到限制。因此，需要寻找潜在的天然化合物作为内皮素受体拮抗剂，这些拮抗剂可以作为双重抑制剂，同时针对 ETA 和 ETB，并具有最高的效率和最小的毒性。因此，本研究旨在通过涉及分子建模、分子动力学和分子对接研究的结构生物信息学方法来优先考虑内皮素受体拮抗剂。随后，针对 ETA 和 ETB 的最佳结合位点，进行高通量虚拟筛选 (HTVS) 与天然化合物数据库。接下来，对共同命中进行结合自由能计算 (MMGBSA) 和 ADMETox 分析。最后，对最有潜力的命中进行基于 MD 的结合稳定性分析和结合自由能分析。同样，也将已知的合成抑制剂对接至受体，并对结果进行分析。从这项研究中可以推断，在天然化合物数据集 (8929 种化合物) 中，只有 4 种常见化合物被确定为命中。在这些化合物中，只有一种化合物 ST075640 超过了所有的优先排序标准，包括 MMGBSA、ADMETox 预测、双重抑制潜力 (ETA 和 ETB)，并且在与博来霉素的结构比较分析中也显示出相似的效率。因此，验证后的命中物有望在调节青光眼条件下的内皮素介导的 IOP、OBF 和 RGC 损伤方面发挥作用。
