Exploring clomiphene inclusion in β-cyclodextrin: a computational approach
Hélio F. Dos Santos
A * , Eloah P. Ávila A and Cleber P. A. Anconi B
A
B
Abstract
Clomiphene (CL) is a widely used antiestrogenic drug for inducing ovulation. The drug is marketed as a mixture of two geometric isomers, E-CL (62%) and Z-CL (38%), with opposing actions and low water solubility. Chemical separation and enhanced solubility can be achieved through cyclodextrin (CD) association. Recent 1H NMR titration experiments have reported the thermodynamic association constant for CL@β-CD as . In this contribution, we conducted a detailed exploration of the association processes underlying this value, resulting in a calculated association constant of based on the multi-equilibrium assumption for a fixed composition. This value was obtained through 720 quantum computational (QC) calculations on configurations selected from molecular dynamics (MD) simulations, which indicated that the Z-CL@β-CD species predominates in solution. To align our results with the experimental data, we considered a fixed composition of the isomers (62% E-CL and 38% Z-CL) when calculating the association constant. Additionally, 1H NMR measurements were conducted for neutral clomiphene and compared to the calculated data for the free guests. For the guest–host inclusion complexes, the 1H NMR chemical shifts were predicted and discussed in relation to the available experimental data. Our findings provide a solid foundation for understanding the inclusion process and introduce the QC/MD multi-equilibrium integrated approach as a valuable theoretical strategy for studying cyclodextrin inclusion compounds.
Keywords: association constant, B97-3c, clomiphene, cyclodextrin, GFN2-xTB, molecular dynamics, multi-equilibrium, NMR.
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