Pharmaceutical Chemistry Laboratory, Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Pilani Campus, Vidya Vihar, Pilani, 333031, RJ, India.
Pharmaceutical Chemistry Laboratory, Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Pilani Campus, Vidya Vihar, Pilani, 333031, RJ, India.
Arch Biochem Biophys. 2024 Jun;756:110019. doi: 10.1016/j.abb.2024.110019. Epub 2024 Apr 28.
Neutral endopeptidase or neprilysin (NEP) cleaves the natriuretic peptides, bradykinin, endothelin, angiotensin II, amyloid β protein, substance P, etc., thus modulating their effects on heart, kidney, and other organs. NEP has a proven role in hypertension, heart disease, renal disease, Alzheimer's, diabetes, and some cancers. NEP inhibitor development has been in focus since the US FDA approved a combination therapy of angiotensin II type 1 receptor inhibitor (valsartan) and NEP inhibitor (sacubitril) for use in heart failure. Considering the importance of NEP inhibitors the present work focuses on the designing of a potential lead for NEP inhibition. A structure-based pharmacophore modelling approach was employed to identify NEP inhibitors from the pool of 1140 chemical entities obtained from the ZINC database. Based on the docking score and pivotal interactions, ten molecules were selected and subjected to binding free energy calculations and ADMET predictions. The top two compounds were studied further by molecular dynamics simulations to determine the stability of the ligand-receptor complex. ZINC0000004684268, a phenylalanine derivative, showed affinity and complex stability comparable to sacubitril. However, in silico studies indicated that it may have poor pharmacokinetic parameters. Therefore, the molecule was optimized using bioisosteric replacements, keeping the phenylalanine moiety intact, to obtain five potential lead molecules with an acceptable pharmacokinetic profile. The works thus open up the scope to further corroborate the present in silico findings with the biological analysis.
中性内肽酶或 Neprilysin（NEP）可切割利钠肽、缓激肽、内皮素、血管紧张素 II、β淀粉样蛋白、P 物质等，从而调节它们对心脏、肾脏和其他器官的作用。NEP 在高血压、心脏病、肾病、阿尔茨海默病、糖尿病和某些癌症中具有已证实的作用。自从美国 FDA 批准血管紧张素 II 型 1 型受体抑制剂（缬沙坦）和 NEP 抑制剂（沙库比曲）联合用于心力衰竭以来，NEP 抑制剂的开发一直是焦点。考虑到 NEP 抑制剂的重要性，本工作重点是设计一种潜在的 NEP 抑制剂先导化合物。采用基于结构的药效团建模方法，从 ZINC 数据库中获得的 1140 种化学实体中筛选 NEP 抑制剂。基于对接评分和关键相互作用，选择了十个分子进行结合自由能计算和 ADMET 预测。前两个化合物进一步通过分子动力学模拟研究，以确定配体-受体复合物的稳定性。苯丙氨酸衍生物 ZINC0000004684268 表现出与沙库比曲相当的亲和力和复合物稳定性。然而，基于计算研究表明，它可能具有较差的药代动力学参数。因此，通过使用生物等排体替换物对分子进行优化，同时保留苯丙氨酸部分，得到五个具有可接受药代动力学特征的潜在先导化合物。这些工作为进一步用生物学分析验证目前的计算结果提供了空间。
