Molecular Structural, Hydrogen Bonding Interactions, and Chemical Reactivity Studies of Ezetimibe-L-Proline Cocrystal Using Spectroscopic and Quantum Chemical Approach.

Preeti Prajapati,Jaya Pandey,Kirti Sinha,Manishkumar R Shimpi,Poonam Tandon

doi:10.3389/fchem.2022.848014

Abstract

Ezetimibe (EZT) being an anticholesterol drug is frequently used for the reduction of elevated blood cholesterol levels. With the purpose of improving the physicochemical properties of EZT, in the present study, cocrystals of ezetimibe with L-proline have been studied. Theoretical geometry optimization of EZT-L-proline cocrystal, energies, and structure–activity relationship was carried out at the DFT level of theory using B3LYP functional complemented by 6-311++G(d,p) basis set. To better understand the role of hydrogen bonding, two different models (EZT + L-proline and EZT + 2L-proline) of EZT-L-proline cocrystal were studied. Spectral techniques (FTIR and FT-Raman) combined with quantum chemical methodologies were successfully implemented for the detailed vibrational assignment of fundamental modes. It is a zwitterionic cocrystal hydrogen bonded with the OH group of EZT and the COO− group of L-proline. The existence and strength of hydrogen bonds were examined by a natural bond orbital analysis (NBO) supported by the quantum theory of atoms in molecule (QTAIM). Chemical reactivity was reflected by the HOMO–LUMO analysis. A smaller energy gap in the cocrystal in comparison to API shows that a cocrystal is softer and chemically more reactive. MEPS and Fukui functions revealed the reactive sites of cocrystals. The calculated binding energy of the cocrystal from counterpoise method was −11.44 kcal/mol (EZT + L-proline) and −26.19 kcal/mol (EZT + 2L-proline). The comparative study between EZT-L-proline and EZT suggest that cocrystals can be better used as an alternative to comprehend the effect of hydrogen bonding in biomolecules and enhance the pharmacological properties of active pharmaceutical ingredients (APIs).

Highlights

The study of an active pharmaceutical ingredient (API) is an essential part of drug discovery and pharmaceutical development
This study demonstrates the frontier molecular orbital (FMOs) analysis, molecular electrostatic potential map (MEPS), and chemical reactivity descriptors for EZT-L-proline cocrystals with the purpose to explore its molecular properties
Difference in bond angles around O4C17-C16 and O4-C17-H40 were observed. The deviations around these bonds occur in cocrystals due to the presence of hydrogen bonds between the hydrogen atom of an aliphatic hydroxyl group of EZT and the oxygen atom (O52) of L-proline, which are not present in APIs

Summary

INTRODUCTION

The study of an active pharmaceutical ingredient (API) is an essential part of drug discovery and pharmaceutical development. In order to demonstrate the quantitative and qualitative interpretation of IR and Raman spectra, the calculated vibrational analysis of EZT + L-proline and EZT + 2L-proline were done using potential energy distribution (PED). This study demonstrates the frontier molecular orbital (FMOs) analysis, molecular electrostatic potential map (MEPS), and chemical reactivity descriptors for EZT-L-proline cocrystals with the purpose to explore its molecular properties. The electronic structure, optimized geometries, vibrational frequencies, natural bond orbital (NBO) analysis, FIGURE 1 | Optimized structure of EZT + L-proline. Molecular electrostatic potential surface (MEPS) of EZT, L-proline, and EZT-L-proline cocrystals were calculated by using density functional theory with B3LYP (Lee et al, 1988; Becke, 1993; Parr and Yang, 1995; Shukla et al, 2017) functional employing 6–311++G(d,p) basis set (Petersson et al, 1988; Petersson and Al-Laham, 1991; Chai and Head-Gordon, 2008; Mendes et al, 2017). Topological and geometrical parameters at the bond critical point (BCP) were studied within the framework of QTAIM (Bader and Cheeseman, 2000)

RESULTS AND DISCUSSION

CONCLUSION

DATA AVAILABILITY STATEMENT