Molecular docking, DFT and antiproliferative properties of 4-(3,4-dimethoxyphenyl)−3-(4-methoxyphenyl)−1-phenyl-1H-pyrazolo[3,4-b]pyridine as potent anticancer agent with CDK2 and PIM1 inhibition potency

IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Drug Development Research Pub Date : 2024-10-28 DOI:10.1002/ddr.70009
Faizah A. Binjubair, Basma S. Almansour, Noha I. Ziedan, Alaa A.-M. Abdel-Aziz, Sara T. Al-Rashood, Mohamed K. Elgohary, Mahmoud S. Elkotamy, Hatem A. Abdel-Aziz
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Abstract

Due to the limited effeteness and safety concerns associated with current cancer treatments, there is a pressing need to develop novel therapeutic agents. 4-(3,4-Dimethoxyphenyl)−3-(4-methoxyphenyl)−1-phenyl-1H-pyrazolo[3,4-b]pyridine (3) was synthesized and Initially screened on 59 cancer cell lines showed promising anticancer activity, so, it was chosen for a 5-dose experiment by the NCI/USA. The GI50 values ranged from 1.04 to 8.02 μM on the entire nine panels (57 cell lines), with a GI50 of 2.70 μM for (MG-MID) panel, indicating an encouraging action. To further explore the molecular attributes of compound 3, we optimized its structure using DFT with the B3LYP/6-31 + + G(d,p) basis set. We have considered vibrational analysis, bond lengths and angles, FMOs, and MEP for the structure. Additionally, pharmacokinetic assessments were conducted using various in-silico platforms to evaluate the compound safety. A molecular modeling study created a kinase profile on 44 different kinases. This allowed us to study our compound's binding affinity to these kinases and compare it to the co-crystallized one. Our findings revealed compound 3 exhibited better binding for half of the tested kinases, suggesting its potential as a multi-kinase inhibitor. To further validate our computational results, we tested compound 3 for its inhibitory effects on CDK2 and PIM1. Compound 3 exhibited an IC50 of 0.30 µM for CDK2 inhibition, making it five times less active than Roscovitine, which has an IC50 of 0.06 µM. However, compound 3 demonstrated slightly better inhibition of PIM1 compared to Staurosporine. These findings suggest that compound 3 is a promising anticancer agent with the potential for further development into a highly active compound.

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4-(3,4-二甲氧基苯基)-3-(4-甲氧基苯基)-1-苯基-1H-吡唑并[3,4-b]吡啶作为具有 CDK2 和 PIM1 抑制效力的强效抗癌剂的分子对接、DFT 和抗增殖特性。
由于目前的癌症治疗方法疗效有限且存在安全隐患,因此迫切需要开发新型治疗药物。我们合成了 4-(3,4-二甲氧基苯基)-3-(4-甲氧基苯基)-1-苯基-1H-吡唑并[3,4-b]吡啶 (3),并对 59 种癌症细胞株进行了初步筛选,结果显示其具有良好的抗癌活性。在整个九个小组(57 个细胞系)中,其 GI50 值介于 1.04 至 8.02 μM 之间,其中(MG-MID)小组的 GI50 值为 2.70 μM,表明其具有令人鼓舞的作用。为了进一步探索化合物 3 的分子属性,我们使用 B3LYP/6-31 + + G(d,p) 基集进行了 DFT 结构优化。我们考虑了结构的振动分析、键长和键角、FMO 和 MEP。此外,我们还利用各种体内平台进行了药代动力学评估,以评价化合物的安全性。分子建模研究建立了 44 种不同激酶的激酶谱。这使我们能够研究化合物与这些激酶的结合亲和力,并将其与共晶体化合物进行比较。我们的研究结果表明,化合物 3 与半数受测激酶的结合力更强,这表明它具有作为多激酶抑制剂的潜力。为了进一步验证计算结果,我们测试了化合物 3 对 CDK2 和 PIM1 的抑制作用。化合物 3 抑制 CDK2 的 IC50 值为 0.30 µM,比 IC50 值为 0.06 µM 的 Roscovitine 低五倍。不过,与 Staurosporine 相比,化合物 3 对 PIM1 的抑制效果稍好。这些研究结果表明,化合物 3 是一种很有前途的抗癌剂,有望进一步开发成为一种高活性化合物。
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来源期刊
CiteScore
6.40
自引率
2.60%
发文量
104
审稿时长
6-12 weeks
期刊介绍: Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.
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