Sayaf Abrar Mohammad, Ullah Khalid Saif, Hameed Jawad Ahmed, Alshammari Abdulrahman, Khan Abbas, Mohammad Anwar, Alghamdi Saeed, Wei Dong-Qing, Yeoh KarKheng
School of Chemical Sciences, Universiti Sains Malaysia, Gelugor, Penang, Malaysia.
Islamia University of Bahawalpur, Bahawalpur, Punjab, Pakistan.
Front Pharmacol. 2023 Aug 21;14:1202128. doi: 10.3389/fphar.2023.1202128. eCollection 2023.
Hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) enzymes are major therapeutic targets of anemia and ischemic/hypoxia diseases. To overcome safety issues, liver failure, and problems associated with on-/off-targets, natural products due to their novel and unique structures offer promising alternatives as drug targets. In the current study, the Marine Natural Products, North African, South African, East African, and North-East African chemical space was explored for HIF-PHD inhibitors discovery through molecular search, and the final hits were validated using molecular simulation and free energy calculation approaches. Our results revealed that CMNPD13808 with a docking score of -8.690 kcal/mol, CID15081178 with a docking score of -8.027 kcal/mol, CID71496944 with a docking score of -8.48 kcal/mol and CID11821407 with a docking score of -7.78 kcal/mol possess stronger activity than the control N-[(4-hydroxy-8-iodoisoquinolin-3-yl)carbonyl]glycine, 4HG (-6.87 kcal/mol). Interaction analysis revealed that the target compounds interact with Gln239, Tyr310, Tyr329, Arg383 and Trp389 residues, and chelate the active site iron in a bidentate manner in PHD2. Molecular simulation revealed that these target hits robustly block the PHD2 active site by demonstrating stable dynamics. Furthermore, the half-life of the Arg383 hydrogen bond with the target ligands, which is an important factor for PHD2 inhibition, remained almost constant in all the complexes during the simulation. Finally, the total binding free energy of each complex was calculated as CMNPD13808-PHD2 -72.91 kcal/mol, CID15081178-PHD2 -65.55 kcal/mol, CID71496944-PHD2 -68.47 kcal/mol, and CID11821407-PHD2 -62.06 kcal/mol, respectively. The results show the compounds possess good activity in contrast to the control drug (4HG) and need further and validation for possible usage as potential drugs against HIF-PHD2-associated diseases.
缺氧诱导因子（HIF）脯氨酰羟化酶结构域（PHD）酶是贫血和缺血/缺氧性疾病的主要治疗靶点。为了克服安全性问题、肝衰竭以及与脱靶/靶效应相关的问题，结构新颖独特的天然产物作为药物靶点提供了有前景的替代方案。在本研究中，通过分子搜索探索了海洋天然产物、北非、南非、东非和东北非的化学空间以发现HIF-PHD抑制剂，并使用分子模拟和自由能计算方法对最终命中的化合物进行了验证。我们的结果表明，对接分数为-8.690 kcal/mol的CMNPD13808、对接分数为-8.027 kcal/mol的CID15081178、对接分数为-8.48 kcal/mol的CID71496944和对接分数为-7.78 kcal/mol的CID11821407比对照N-[(4-羟基-8-碘异喹啉-3-基)羰基]甘氨酸（4HG，-6.87 kcal/mol）具有更强的活性。相互作用分析表明，目标化合物与Gln239、Tyr310、Tyr329、Arg383和Trp389残基相互作用，并以双齿方式螯合PHD2中的活性位点铁。分子模拟表明，这些目标命中化合物通过展示稳定的动力学有力地阻断了PHD2活性位点。此外，在模拟过程中，与目标配体形成的Arg383氢键的半衰期（这是抑制PHD2的一个重要因素）在所有复合物中几乎保持恒定。最后，计算出每个复合物的总结合自由能分别为CMNPD13808-PHD2 -72.91 kcal/mol、CID15081178-PHD2 -65.55 kcal/mol、CID71496944-PHD2 -68.47 kcal/mol和CID11821407-PHD2 -62.06 kcal/mol。结果表明，与对照药物（4HG）相比，这些化合物具有良好的活性，需要进一步研究和验证其作为抗HIF-PHD2相关疾病潜在药物的可能用途。
