Bhardwaj Vijay Kumar, Singh Rahul, Sharma Jatin, Das Pralay, Purohit Rituraj
Structural Bioinformatics Lab, CSIR-Institute of Himalayan Bioresource Technology (CSIR-IHBT), Palampur, Himachal Pradesh, 176061, India; Biotechnology division, CSIR-IHBT, Palampur, Himachal Pradesh, 176061, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-IHBT Campus, Palampur, Himachal Pradesh, 176061, India.
Structural Bioinformatics Lab, CSIR-Institute of Himalayan Bioresource Technology (CSIR-IHBT), Palampur, Himachal Pradesh, 176061, India; Biotechnology division, CSIR-IHBT, Palampur, Himachal Pradesh, 176061, India.
Comput Methods Programs Biomed. 2020 Oct;194:105494. doi: 10.1016/j.cmpb.2020.105494. Epub 2020 May 15.
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.
双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，由于其参与病理疾病的发现，最近已成为一种重要的药物靶点。开发新型高效的DYRK1A抑制剂将有助于阐明相关疾病的分子机制。它将为分子靶向蛋白提供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稠合苯并环庚烯（PBS）化合物文库与DYRK1A受体进行对接。此外，进行分子力学-泊松玻尔兹曼表面积（MM-PBSA）估算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比较。结果：本研究报告Ligand15、Ligand14和Ligand11为强效抑制剂，与2C3相比，它们表现出更高的配体效率、结合亲和力、亲脂性配体效率和良好的扭转值。结论：所述方法揭示了一种独特的活性位点结合机制。活性位点内的结合相互作用表明，所选分子与标准分子相比具有显著的相互作用，这导致了抑制DYRK1A的潜在化合物的产生。
