Crystal structures, NCI-RDG, Hirshfeld surface and energy framework analysis of tetra aryl substitute bispidine and oxaquinuclidine core containing derivatives: A potential COVID-19 drug candidate

• Published in: Journal of molecular structure 2025-02, Vol.1321, p.140202, Article 140202
• Main Authors: Vengatesh, G., Vinushya, N., Jeyaprakash, G.M., Mohini, Antra, Mondal, Priyanshi, Reddy, Rajashekar, Shriram, Zade Omkar
• Format: Article
• Language: English
• Subjects: COVID-19 protein docking; Crystal structure; Hirshfeld surface; Interaction energy; NCI-RDG; Piperidine
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.140202

•Hirshfeld surface analysis reveals that hydrogen bonding is essential for both types of crystal packing.•Energy framework analysis confirms crystals stabilized through electrostatic energy contribution.•The higher mechanical stability of the packed crystal was investigated using void analysis.•The non-covalent interaction sites of the molecule are validated through RDG analysis.•The reported piperidine and oxaquinuclidine core compounds exhibit significant binding interaction with the COVID-19 proteins. Two of the title compounds are crystallized in P21/c and monoclinic face groups. Each crystal unit cell has four molecules. There are two piperidine rings: one in the chair conformation and another one in the boat conformation. The piperidine nitrogen in the boat conformation is joined to the oxygen-containing chair conformation piperidine ring to produce the oxaquinuclidine ring (-N-CH2O-). Furthermore, because of the steric barrier between rings, all aryl groups are oriented in an equatorial position. The crystal network is maintained through several interactions, including C—H⋯O/N/Cl/π. The crystal void and interaction energy studies gave additional evidence of the strength of the crystal packing and intermolecular linkage. Crystal 3b has less cavity than crystal 3c, indicating that it is densely packed. The dispersion energy contribution dominates the stability, according to the analysis of the electrostatic, dispersion, and total energy frameworks. Reduced density gradient (RDG), electron localization function (ELF), and localized orbital locator (LOL) analysis were used to determine the molecular interaction, electron pair density, and maximally localized orbitals overlapping sites, respectively. This approach reveals that oxaquinuclidine ring steric hindrance and the electron densities throughout the molecules. Density function theory (DFT) provides more evidence for the ring's orientation and the molecules' reactivity. A molecular docking investigation of four essential COVID-19 proteins was carried out using these theoretical ideas. This investigation demonstrates that each protein's reactivity varies; certain proteins have more interaction with high electron density molecules (electron-donating substituent), while others have more interaction with low electron density molecules (electron-withdrawing substituent). The ADMET and drug-likeness investigations reveal that methoxy group substituted molecules perfectly correlate with the required pharma