Maheshwari Arti, Saraswat Harish, Upadhyay Santosh Kumar
Department of Chemistry, Institute of Applied Sciences, Mangalayatan University, Aligarh, U.P., India.
CSIR-Institute of Genomics & Integrative Biology, New Delhi, India.
Chirality. 2017 Aug;29(8):451-457. doi: 10.1002/chir.22712. Epub 2017 Jun 23.
A major challenge in pharmaceuticals for clinical applications is to alter the solubility, stability, and toxicity of drug molecules in living systems. Cyclodextrins (CDs) have the ability to form host-guest inclusion complexes with pharmaceuticals for further development of new drug formulations. The inclusion complex of clomiphene citrate (CL), a poorly water-soluble drug, with native β-cyclodextrin (β-CD) was characterized by a one and two-dimensional nuclear magnetic resonance (NMR) spectroscopic approach and also by molecular docking techniques. Here we report NMR and a computational approach in preferential isomeric selection of CL, which exists in two stereochemical isomers, enclomiphene citrate (ENC; E isomer) and zuclomiphene citrate (ZNC; Z isomer) with β-CD. β-CD cavity protons, namely, H-3' and H-5', experienced shielding in the presence of CL. The aromatic ring protons of the CL molecule were observed to be deshielded in the presence of β-CD. The stoichiometric ratio of the β-CD:CL inclusion complex was observed by NMR and found to be 1:1. The overall binding constant of β-CD:CL inclusion complexes was based on NMR chemical shifts and was calculated to be 50.21 M . The change in Gibb's free energy (∆G) was calculated to be -9.80 KJ mol . The orientation and structure of the β-CD:CL inclusion complexes are proposed on the basis of NMR and molecular docking studies. 2D H- H ROESY confirmed the involvement of all three aromatic rings of CL in the inclusion complexation with β-CD in the solution, confirming the multiple equilibria between β-CD and CL. Molecular docking and 2D H- H ROESY provide insight into the inclusion complexation of two isomers of CL into the β-CD cavity. A molecular docking technique further provided the different binding affinities of the E and Z isomers of CL with β-CD and confirmed the preference of the Z isomer binding for β-CD:CL inclusion complexes. The study indicates that the formation of a hydrogen bond between -O- of CL and the hydrogen atom of the hydroxyl group of β-CD was the main factor for noncovalent β-CD:CL inclusion complex formation and stabilization in the aqueous phase.
临床应用药物面临的一个主要挑战是改变药物分子在生物系统中的溶解度、稳定性和毒性。环糊精（CDs）能够与药物形成主客体包合物，以进一步开发新的药物制剂。采用一维和二维核磁共振（NMR）光谱方法以及分子对接技术对难溶性药物枸橼酸氯米芬（CL）与天然β-环糊精（β-CD）的包合物进行了表征。在此，我们报告了NMR和一种计算方法用于优先选择CL的异构体，CL存在两种立体化学异构体，即枸橼酸恩氯米芬（ENC；E异构体）和枸橼酸珠氯米芬（ZNC；Z异构体）与β-CD。β-CD腔质子，即H-3'和H-5'，在CL存在下受到屏蔽。观察到CL分子的芳香环质子在β-CD存在下发生去屏蔽。通过NMR观察到β-CD:CL包合物的化学计量比为1:1。β-CD:CL包合物的总结合常数基于NMR化学位移计算得出，为50.21 M⁻¹。吉布斯自由能变化（∆G）计算为 -9.80 kJ mol⁻¹。基于NMR和分子对接研究提出了β-CD:CL包合物的取向和结构。二维¹H-¹H ROESY证实了CL的所有三个芳香环参与了在溶液中与β-CD的包合络合，证实了β-CD和CL之间的多重平衡。分子对接和二维¹H-¹H ROESY深入了解了CL的两种异构体进入β-CD腔的包合络合情况。分子对接技术进一步提供了CL的E和Z异构体与β-CD的不同结合亲和力，并证实了Z异构体对β-CD:CL包合物结合的偏好。该研究表明，CL的 -O- 与β-CD羟基的氢原子之间形成氢键是水相中β-CD:CL非共价包合物形成和稳定的主要因素。
