N. S. Zefirov
Department of Chemistry, M. V. Lomonosov Moscow State University, Moscow 119991, Russia

Abstract:

Design of new drug molecules is a sophisticated process involving in the first steps the application of molecular modeling and QSAR techniques, virtual screening and molecular docking. The joint application of these approaches provides deeper understanding of both structure-activity relationships and ligand-receptor interactions as well as facilitates lead finding and optimization.

For the design of new neuroprotective compounds the molecular models have been built of all domains in closed and open forms of metabotropic (mGluR1-8) and ionotropic (NMDA) glutamate receptors, adenosine, melatonin, GABAA and GABAC receptors. The docking of known agonists, antagonists, modulators, and channel blockers into the models was used to reveal binding modes of ligands and to explain known structure-activity relationships. MFTA and CoMFA models were developed for the binding of antagonists, modulators, and channel blockers. The artificial neural networks trained using fragmental descriptors were successfully applied to the classification of neuroprotective compounds. The combined application of QSAR techniques and molecular modeling enabled the evaluation of ligand structural features important for high affinity to the receptors.

Efficient protection against diverse group of neurological disorders related to glutamate excitotoxicity can be achieved by a specific blockade of calcium ion influx via activated NMDA receptor. On the other hand, a slight potentiation of AMPA receptors can improve cognition function deficit developed in some neurodegenerative diseases such as Alzheimer’s disease-type dementia. This hypothesis was successfully used in the design of new neuroprotectors with cognition enhancing properties. The focused library of MK-801 flexible analogs was created using both QSAR and docking studies. Hit compounds, in animal model of AD-type dementia simulated by cholinotoxin AF64A, revealed a significant improvement of memory in Morris water maze test while psychotomimetic side effects, in contrast to MK-801, were absent.

On the basis of 3D structure of the positive modulator binding site of AMPA receptor, a series of compounds has been designed using molecular docking techniques and detailed manual refinement of structures. Extraordinary high potency of the designed compounds starting from picomolar had been revealed – absolute record among all currently known positive AMPA receptor modulators.

References:

N.S.Zefirov, V.A.Palyulin, Molecular Modelling of Central Nervous System Receptors, Mendeleev Commun., 2010, 20, 243-248.