Synthesis of Pregn-5-en-3β-ol-20-one derivatives via Heck reaction: A combined molecular docking, DFT, and NCI-RDG study

Abstract

Synthesis of C-3 pregnenolone derivatives using Steglich and Heck reaction has been reported, were characterized by ¹HNMR , ¹³CNMR , FT-IR, and ESI-MS. Molecular docking studies were carried out to investigate the inhibitory action of steroidal derivatives against the breast cancer cell proteins estrogen receptor alpha (PDB ID: 3ERT) and progesterone receptor (PDB ID: 4OAR). The result of the docking exhibited a significant inhibitory action against the breast cancer cell proteins and the binding energy (ΔG) values of 1, 2, 3A, 3B and 3C against the protein 3ERT were found to be -7.76, -8.02, -8.49, -9.51 and -8.31 Kcal/mol, respectively and the binding energy (ΔG) values of 1, 2, 3A, 3B and 3C against the protein 4OAR were found to be -7.74, -9.03, -9.72, -9.29 and -9.53 Kcal/mol, respectively which showed that compound 3B was more potent against 3ERT than the parent and other synthesized compounds and compound 3A was more potent against 4OAR than the parent and other synthesized compounds. Quantum chemical calculations of compounds 2, 3A, 3B and 3C were performed in the ground state using the DFT of B3LYP level with 6–31G(d,p) basis set. The electronic properties, including HOMO and LUMO energy levels, were investigated using the time-dependent density functional theory (TD-DFT) method. The chemical reactivity of the synthesized compounds was analyzed through both global and local reactivity descriptors. Furthermore, non-covalent interactions (NCIs) index analysis based on the Reduced Density Gradient (RDG) approach revealed that the stability of the derivatives is primarily attributed to weak intermolecular interactions, such as CH⋯O hydrogen bonds, along with C⋯H and H⋯H van der Waals interactions. All derivatives' ADMET analyses have also been examined.