Rahman Adhip, Ali Mohammad Tuhin, Shawan Mohammad Mahfuz Ali Khan, Sarwar Mohammed Golam, Khan Mohammad A K, Halim Mohammad A
Division of Computer Aided Drug Design, Green Research Centre, BICCB, 38 Green Road West, Dhaka, 1205 Bangladesh.
Division of Computer Aided Drug Design, Green Research Centre, BICCB, 38 Green Road West, Dhaka, 1205 Bangladesh ; Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000 Bangladesh.
Springerplus. 2016 Aug 12;5(1):1346. doi: 10.1186/s40064-016-2996-5. eCollection 2016.
A series of halogen-directed donepezil drugs has been designed to inhibit acetyl cholinesterase (AChE). Density Functional theory (DFT) has been employed to optimize the chair as well as boat conformers of the parent drug and modified ligands at B3LYP/MidiX and B3LYP/6-311G + (d,p) level of theories. Charge distribution, dipole moment, enthalpy, free energy and molecular orbitals of these ligands are also investigated to understand how the halogen-directed modifications impact the ligand structure and govern the non-bonding interactions with the receptors. Molecular docking calculation has been performed to understand the similarities and differences between the binding modes of unmodified and halogenated chair-formed ligands. Molecular docking indicated donepezil and modified ligands had non-covalent interactions with hydrophobic gorges and anionic subsites of AChE. The -CF3-directed ligand possessed the most negative binding affinity. Non-covalent interactions within the ligand-receptor systems were found to be mostly hydrophobic and π- stacking type. F, Cl and -CF3 containing ligands emerge as effective and selective AChE inhibitors, which can strongly interact with the two active sites of AChE. In addition, we have also investigated selected pharmacokinetic parameters of the parent and modified ligands.
已设计出一系列卤素导向的多奈哌齐药物以抑制乙酰胆碱酯酶（AChE）。采用密度泛函理论（DFT）在B3LYP/MidiX和B3LYP/6 - 311G + (d,p)理论水平上优化母体药物和修饰配体的椅式以及船式构象。还研究了这些配体的电荷分布、偶极矩、焓、自由能和分子轨道，以了解卤素导向修饰如何影响配体结构并控制与受体的非键相互作用。进行了分子对接计算，以了解未修饰和卤化椅式配体结合模式之间的异同。分子对接表明多奈哌齐和修饰配体与AChE的疏水峡谷和阴离子亚位点存在非共价相互作用。-CF3导向的配体具有最负的结合亲和力。发现配体 - 受体系统内的非共价相互作用主要是疏水和π堆积类型。含F、Cl和 -CF3的配体是有效的选择性AChE抑制剂，可与AChE的两个活性位点强烈相互作用。此外，我们还研究了母体和修饰配体的选定药代动力学参数。
