NMDA Receptor as a Molecular Target for Central Nervous System Disorders: The Advances and Contributions of Molecular Modeling
Pp. 211-249 (39)
Marcos Vinicius Santana, Helena Carla Castro and Paula Alvarez Abreu
The N-methyl-D-aspartate receptor (NMDAR) is a glutamate receptor that
mediates important physiological functions in the central nervous system (CNS).
However, the overstimulation of this receptor is associated with neurodegenerative
disorders, including Parkinson, Huntington and Alzheimer diseases. In this new
millennium, diseases causing progressive neuronal loss and death have become more
frequent and the current therapy still presents several adverse effects and does not
block disease progression. In this chapter, we discuss the role of NMDAR in
neurodegenerative disorders and its potential as a therapeutic target, the advances in the
development of NMDAR antagonists and the contributions of molecular modeling in
this field. NMDAR structure is already known allowing the use of molecular modeling
tools for the development of new NMDAR antagonists. Studies involving the use of
structure based drug-design methods as molecular docking and virtual screening for
discovering new NMDAR antagonists were reviewed here; as well as the in silico
evaluation of pharmacokinetic and toxicological properties. CNS drugs should be
capable of effectively cross the blood brain barrier to be active and the early evaluation
of the safety profile of these compounds is extremely important to reduce the time and
costs to develop new drugs for neurodegenerative disease therapy.
ADMET prediction, Central nervous system disease, Docking,
Glutamate excitotoxicity, GluN2B antagonists, Molecular modeling, Neurodegenerative
diseases, NMDA receptor, Structure-based drug design, Virtual
LAMCIFAR, Laboratorio de Modelagem Molecular e Pesquisa em Ciencias Farmaceuticas, Universidade Federal do Rio de Janeiro, Campus UFRJ-Macae, RJ, Brazil.