An in-silico investigation based on molecular simulations of novel and potential brain-penetrant GluN2B NMDA receptor antagonists as anti-stroke therapeutic agents

• Published in: Journal of biomolecular structure & dynamics 2024-08, Vol.42 (12), p.6174-6188
• Main Authors: El fadili, Mohamed, Er-rajy, Mohammed, Ali Eltayb, Wafa, Kara, Mohammed, Imtara, Hamada, Zarougui, Sara, Al-Hoshani, Nawal, Hamadi, Abdullah, Elhallaoui, Menana
• Format: Article
• Language: English
• Subjects: ADMET; BBB; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain - drug effects; Brain - metabolism; CADD; CNS; Drug Design; Humans; Ligands; molecular docking; Molecular Docking Simulation; molecular dynamics; Molecular Dynamics Simulation; NMDA; Protein Binding; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - chemistry; Receptors, N-Methyl-D-Aspartate - metabolism; Stroke - drug therapy; Stroke - metabolism
• ISSN: 0739-1102; 1538-0254; 1538-0254
• DOI: 10.1080/07391102.2023.2232024

GluN2B-induced activation of NMDA receptors plays a key function in central nervous system (CNS) disorders, including Parkinson, Alzheimer, and stroke, as it is strongly involved in excitotoxicity, which makes selective NMDA receptor antagonists one of the potential therapeutic agents for the treatment of neurodegenerative diseases, especially stroke. The present study aims to examine a structural family of thirty brain-penetrating GluN2B N-methyl-D-aspartate (NMDA) receptor antagonists, using virtual computer-assisted drug design (CADD) to discover highly candidate drugs for ischemic strokes. Initially, the physicochemical and ADMET pharmacokinetic properties confirmed that C13 and C22 compounds were predicted as non-toxic inhibitors of CYP2D6 and CYP3A4 cytochromes, with human intestinal absorption (HIA) exceeding 90%, and designed to be as efficient central nervous system (CNS) agents due to the highest probability to cross the blood-brain barrier (BBB). Compared to ifenprodil, a co-crystallized ligand complexed with the transport protein encoded as 3QEL.pdb, we have noticed that C13 and C22 chemical compounds were defined by good ADME-Toxicity profiles, meeting Lipinski, Veber, Egan, Ghose, and Muegge rules. The molecular docking results indicated that C22 and C13 ligands react specifically with the amino acid residues of the NMDA receptor subunit GluN1 and GluN2B. These intermolecular interactions produced between the candidate drugs and the targeted protein in the B chain remain stable over 200 nanoseconds of molecular dynamics simulation time. In conclusion, C22 and C13 ligands are highly recommended as anti-stroke therapeutic drugs due to their safety and molecular stability towards NMDA receptors. Communicated by Ramaswamy H. Sarma