Debnath Abhijit, Rani Anjna, Mazumder Rupa, Mazumder Avijit, Singh Rajesh Kumar, Sharma Shalini, Srivastava Shikha, Chaudhary Hema, Mishra Rashmi, Khurana Navneet, Sanchitra Jahanvi, Jan Sk Ashif
Noida Institute of Engineering and Technology [Pharmacy Institute], 19 Knowledge Park-II, Institutional Area, Greater Noida, Uttar Pradesh, India.
Department of Dravyaguna, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
Curr Comput Aided Drug Des. 2024 Oct 14. doi: 10.2174/0115734099278007241004105500.
To Discover novel PTP1B inhibitors by high-throughput virtual screening Background: Type 2 Diabetes is a significant global health concern. According to projections, the estimated number of individuals affected by the condition will reach 578 million by the year 2030 and is expected to further increase to 700 million deaths by 2045. Protein Tyrosine Phosphatase 1B is an enzymatic protein that has a negative regulatory effect on the pathways involved in insulin signaling. This regulatory action ultimately results in the development of insulin resistance and the subsequent elevation of glucose levels in the bloodstream. The proper functioning of insulin signaling is essential for maintaining glucose homeostasis, whereas the disruption of insulin signaling can result in the development of type 2 diabetes. Consequently, we sought to utilize PTP1B as a drug target in this investigation.
The purpose of our study was to identify novel PTP1B inhibitors as a potential treatment for managing type 2 diabetes.
To discover potent PTP1B inhibitors, we have screened the Maybridge HitDiscover database by SBVS. Top hits have been passed based on various drug-likeness rules, toxicity predictions, ADME assessment, Consensus Molecular docking, DFT, and 300 ns MD Simulations.
Two compounds have been identified with strong binding affinity at the active site of PTP1B along with drug-like properties, efficient ADME, low toxicity, and high stability.
The identified molecules could potentially manage T2DM effectively by inhibiting PTP1B, providing a promising avenue for therapeutic strategies.
通过高通量虚拟筛选发现新型蛋白酪氨酸磷酸酶1B（PTP1B）抑制剂
2型糖尿病是全球重大的健康问题。据预测，到2030年受该疾病影响的人数估计将达到5.78亿，预计到2045年将进一步增至7亿人死亡。蛋白酪氨酸磷酸酶1B是一种酶蛋白，对胰岛素信号传导途径具有负调节作用。这种调节作用最终导致胰岛素抵抗的发展以及随后血液中葡萄糖水平的升高。胰岛素信号的正常功能对于维持葡萄糖稳态至关重要，而胰岛素信号的破坏会导致2型糖尿病的发展。因此，在本研究中我们试图将PTP1B用作药物靶点。
我们研究的目的是鉴定新型PTP1B抑制剂作为治疗2型糖尿病的潜在疗法。
为了发现有效的PTP1B抑制剂，我们通过基于结构的虚拟筛选（SBVS）对Maybridge HitDiscover数据库进行了筛选。根据各种类药规则、毒性预测、药物代谢动力学（ADME）评估、一致性分子对接、密度泛函理论（DFT）和300纳秒分子动力学（MD）模拟筛选出顶级命中化合物。
已鉴定出两种化合物，它们在PTP1B的活性位点具有很强的结合亲和力，同时具有类药性质、高效的ADME、低毒性和高稳定性。
所鉴定的分子可能通过抑制PTP1B有效治疗2型糖尿病，为治疗策略提供了一条有前景的途径。
