当前位置: X-MOL 学术Comput. Methods Programs Biomed. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Structural based study to identify new potential inhibitors for dual specificity tyrosine-phosphorylation- regulated kinase.
Computer Methods and Programs in Biomedicine ( IF 6.1 ) Pub Date : 2020-05-15 , DOI: 10.1016/j.cmpb.2020.105494
Vijay Kumar Bhardwaj 1 , Rahul Singh 2 , Jatin Sharma 2 , Pralay Das 3 , Rituraj Purohit 1
Affiliation  

Background and Objectives The Dual-specificity tyrosine-phosphorylation regulated kinase-1A (DYRK1A) a serine/threonine kinase that has freshly gained recognition as an essential drug target due to the discovery of its involvement in pathological diseases. The development of new potent inhibitors of DYRK1A would contribute to clarify the molecular mechanisms of associated diseases. It would administer a new lead compound for molecular-targeted protein, which was the primary focus of our study.

Methods The library of in-house synthesized pyrrolone-fused benzosuberene (PBS) compounds was docked with DYRK1A receptor. Further, molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) estimations were conducted to confirm our docking outcomes and compared the stability of chosen complexes with the 2C3 (standard molecule) complex.

Results This study reports Ligand15, Ligand14, and Ligand11 as potent inhibitors which showed higher ligand efficiency, binding affinity, lipophilic ligand efficiency, and favorable torsion values as compared to 2C3.

Conclusion The stated methodologies revealed a unique mechanism of active site binding. The binding interactions within the active site showed that the chosen molecules had notable interactions than the standard molecule, which led to the generation of potential compounds to inhibit DYRK1A.



中文翻译:

基于结构的研究,以鉴定新型的双重特异性酪氨酸磷酸化调节激酶潜在抑制剂。

背景和目的双重特异性酪氨酸磷酸化调节激酶-1A(DYRK1A)是一种丝氨酸/苏氨酸激酶,由于发现其参与病理性疾病而得到了新的认可,成为必需的药物靶标。新型DYRK1A高效抑制剂的开发将有助于阐明相关疾病的分子机制。它将为分子靶向蛋白使用一种新的先导化合物,这是我们研究的主要重点。

方法将内部合成的吡咯烷酮融合的苯并亚戊烯(PBS)化合物库与DYRK1A受体对接。此外,进行了分子力学-泊松玻耳兹曼表面积(MM-PBSA)估计以确认我们的对接结果,并将所选复合物与2C3(标准分子)复合物的稳定性进行了比较。

结果这项研究报告Ligand15,Ligand14和Ligand11是有效的抑制剂,与2C3相比,具有更高的配体效率,结合亲和力,亲脂性配体效率和良好的扭转值。

结论所述方法揭示了活性位点结合的独特机制。活性位点内的结合相互作用表明,所选择的分子与标准分子相比具有显着的相互作用,这导致了潜在化合物的抑制DYRK1A的产生。

更新日期:2020-05-15
down
wechat
bug