Mahema Sivakumar, Jency Roshni, Sheikh F Ahmad, Sabry M Attia, Magesh Ramasamy, Shiek S S J Ahmed
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引用次数: 0
摘要
背景:PARP抑制剂奥拉帕尼对乳腺癌患者有效;然而,由于耐药机制,其在三阴性乳腺癌(TNBC)中的疗效降低。最近的研究表明,CDK4抑制剂palbociclib可以增强癌细胞对PARP抑制剂的敏感性。我们将帕博西尼的吡啶[3,4-d]嘧啶段与奥拉帕尼的酞嗪酮环结合,设计了43个杂化化合物。药代动力学分析和分子对接显示,化合物17与天然抑制剂相比,与PARP1和CDK4的结合亲和力分别为- 8.42 kcal/mol和- 10.05 kcal/mol,是一个很有希望的候选者。此外,诱导匹配对接验证了其与天然抑制剂相比的优越性。500 ns以上的分子动力学模拟证实了化合物17与两个靶点的结构稳定性。此外,QM/MM、DFT、TD-DFT和MEP分析对电荷转移和电子跃迁产生了重要的见解,增强了我们对杂化化合物的电子和键性质的理解。方法:为了方便43种杂化化合物的设计,使用ChemSketch,并使用Maestro Schrödinger套件(v13.5)的QikProp模块对这些化合物的药代动力学性质进行预测。我们使用对接方法检查了蛋白质-配体复合物的结合亲和力,并使用Maestro Schrödinger suite (v13.5)中的Desmond模块进行了分子动力学模拟,验证了蛋白质-配体复合物的稳定性。在B3LYP/6-31G**水平上进行了量子力学分析,以阐明DFT/TD-DFT、分子静电势、Mulliken电荷、化学描述子、NBO和NLO性质。
Fused pyrido[3,4-D]pyrimidine moiety with phthalazinone ring accelerate dual inhibition of PARP1 and CDK4 in triple-negative breast cancer: a hybrid design with computational investigation through molecular modeling and quantum mechanics.
Context: The PARP inhibitor olaparib is effective in breast cancer patients; however, its efficacy is reduced in triple-negative breast cancer (TNBC) due to mechanisms of drug resistance. Recent studies demonstrate that the CDK4 inhibitor palbociclib can enhance the sensitivity of cancer cells to PARP inhibitors. We designed 43 hybrid compounds by combining the pyrido[3,4-d]pyrimidine moiety from palbociclib with the phthalazinone ring from olaparib. Pharmacokinetic profiling and molecular docking revealed compound 17 as a promising candidate, demonstrating a binding affinity of - 8.42 kcal/mol with PARP1 and - 10.05 kcal/mol with CDK4, in contrast to the native inhibitors. Furthermore, the induced fit docking validated its superiority compared to the native inhibitors. Molecular dynamics simulations over 500 ns confirmed the structural stability of compound 17 with both targets. Moreover, the QM/MM, DFT, TD-DFT, and MEP analyses yielded significant insights into charge transfer and electronic transitions, augmenting our understanding of the electronic and bonding properties of the hybrid compound.
Methods: To facilitate the design of 43 hybrid compounds, ChemSketch was utilized, and QikProp, a module of the Maestro Schrödinger suite (v13.5), was used to make predictions regarding the pharmacokinetic properties of these compounds. We checked the binding affinities using docking methods and the stability of the protein-ligand complex using molecular dynamics simulations with Desmond module in Maestro Schrödinger suite (v13.5). Quantum mechanical analyses at the B3LYP/6-31G** level were conducted to elucidate the DFT/TD-DFT, molecular electrostatic potential, Mulliken charges, chemical descriptors, NBO, and NLO properties.
期刊介绍:
The Journal of Molecular Modeling focuses on "hardcore" modeling, publishing high-quality research and reports. Founded in 1995 as a purely electronic journal, it has adapted its format to include a full-color print edition, and adjusted its aims and scope fit the fast-changing field of molecular modeling, with a particular focus on three-dimensional modeling.
Today, the journal covers all aspects of molecular modeling including life science modeling; materials modeling; new methods; and computational chemistry.
Topics include computer-aided molecular design; rational drug design, de novo ligand design, receptor modeling and docking; cheminformatics, data analysis, visualization and mining; computational medicinal chemistry; homology modeling; simulation of peptides, DNA and other biopolymers; quantitative structure-activity relationships (QSAR) and ADME-modeling; modeling of biological reaction mechanisms; and combined experimental and computational studies in which calculations play a major role.