Kaur Maninder, Singh Manjinder, Silakari Om
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences & Drug Research, Punjabi University, Patiala, Punjab 147002, India.
Future Med Chem. 2017 Jul;9(11):1193-1211. doi: 10.4155/fmc-2017-0037. Epub 2017 Jul 19.
Autoimmune disorders have complex pathophysiology and focus is laid on the development of multitargeted agents. Two well-established kinases: SYK and JAK3, were considered to design dual inhibitors as potential therapeutics using various molecular-modeling approaches. Mehodology: Pharmacophore models for SYK and JAK3 were generated using oxindole-based inhibitors. Furthermore, an in-house database was designed that was screened against the best selected models. The obtained hits were employed for docking analysis and subjected to MM-GBSA analysis and molecular dynamic simulation.
Top five oxindole derivatives were synthesized and evaluated for in vitro SYK and JAK3 activity. The most active compound 4a was evaluated for in vivo antiarthritic activity. It showed significant anti-arthritic activity.
Thus, the designed inhibitors resulted in potential therapeutic agents for rheumatoid arthritis.
自身免疫性疾病具有复杂的病理生理学，多靶点药物的研发受到关注。两种成熟的激酶：脾酪氨酸激酶（SYK）和Janus激酶3（JAK3），被考虑使用各种分子建模方法设计双抑制剂作为潜在治疗药物。方法：使用基于氧化吲哚的抑制剂生成SYK和JAK3的药效团模型。此外，设计了一个内部数据库，并针对最佳选择的模型进行筛选。获得的命中化合物用于对接分析，并进行MM-GBSA分析和分子动力学模拟。
合成了前五种氧化吲哚衍生物，并评估了其体外SYK和JAK3活性。对活性最高的化合物4a进行了体内抗关节炎活性评估。它显示出显著的抗关节炎活性。
因此，所设计的抑制剂有望成为类风湿性关节炎的治疗药物。
