Tackling Stereochemistry in Drug Molecules with Vibrational Optical Activity

Author(s)

Bogaerts, Jonathan ^[1] ; Aerts, Roy ^[1] ; Vermeyen, Tom ^{[1, 2]} ; Johannessen, Christian ^[1] ; Herrebout, Wouter ^[1] ; Batista, Joao M. ^[3]

Affiliation

^[1] Univ Antwerp, Dept Chem, B-2020 Antwerp - Belgium

^[2] Univ Ghent, Dept Chem, B-9000 Ghent - Belgium

^[3] Univ Fed Sao Paulo, Inst Sci & Technol, BR-12231280 Sao Jose Dos Campos, SP - Brazil

• Document type: Review article
• Source: PHARMACEUTICALS; v. 14, n. 9 SEP 2021.
• Web of Science Citations: 0

Abstract

Chirality plays a crucial role in drug discovery and development. As a result, a significant number of commercially available drugs are structurally dissymmetric and enantiomerically pure. The determination of the exact 3D structure of drug candidates is, consequently, of paramount importance for the pharmaceutical industry in different stages of the discovery pipeline. Traditionally the assignment of the absolute configuration of druggable molecules has been carried out by means of X-ray crystallography. Nevertheless, not all molecules are suitable for single-crystal growing. Additionally, valuable information about the conformational dynamics of drug candidates is lost in the solid state. As an alternative, vibrational optical activity (VOA) methods have emerged as powerful tools to assess the stereochemistry of drug molecules directly in solution. These methods include vibrational circular dichroism (VCD) and Raman optical activity (ROA). Despite their potential, VCD and ROA are still unheard of to many organic and medicinal chemists. Therefore, the present review aims at highlighting the recent use of VOA methods for the assignment of the absolute configuration of chiral small-molecule drugs, as well as for the structural analysis of biologics of pharmaceutical interest. A brief introduction on VCD and ROA theory and the best experimental practices for using these methods will be provided along with selected representative examples over the last five years. As VCD and ROA are commonly used in combination with quantum calculations, some guidelines will also be presented for the reliable simulation of chiroptical spectra. Special attention will be paid to the complementarity of VCD and ROA to unambiguously assess the stereochemical properties of pharmaceuticals. (AU)

• FAPESP's process: 19/22319-5 - Vibrational circular dichroism spectral markers: facilitating absolute configuration assignment of natural products
• Grantee: João Marcos Batista Junior
• Support Opportunities: Regular Research Grants