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

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.

Pinocembrin: a novel natural compound with versatile pharmacological and biological activities.

Pinocembrin (5,7-dihydroxyflavanone) is one of the primary flavonoids isolated from the variety of plants, mainly from Pinus heartwood, Eucalyptus, Populus, Euphorbia, and Sparattosperma leucanthum, in the diverse flora and purified by various chromatographic techniques. Pinocembrin is a major flavonoid molecule incorporated as multifunctional in the pharmaceutical industry. Its vast range of pharmacological activities has been well researched including antimicrobial, anti-inflammatory, antioxidant, and anticancer activities. In addition, pinocembrin can be used as neuroprotective against cerebral ischemic injury with a wide therapeutic time window, which may be attributed to its antiexcitotoxic effects. Pinocembrin exhibits pharmacological effects on almost all systems, and our aim is to review the pharmacological and therapeutic applications of pinocembrin with specific emphasis on mechanisms of actions. The design of new drugs based on the pharmacological effects of pinocembrin could be beneficial. This review suggests that pinocembrin is a potentially promising pharmacological candidate, but additional studies and clinical trials are required to determine its specific intracellular sites of action and derivative targets in order to fully understand the mechanism of its anti-inflammatory, anticancer, and apoptotic effects to further validate its medical applications.