In silico modeling of human dopamine transporter and design of novel inhibitors
Kemal Yelekci and Teodora Djikic
Kadir Has University, Turkey
: J Pharm Drug Deliv Res
Abstract
Parkinson’s disease is a common neurodegenerative disorder of the central nervous system. It is characterized by the loss of dopamine-generating neurons in the substantia nigra and corpus striatum (which leads to the decreasing level of dopamine) and accumulation of α-synuclein aggregates in the brain. Presently, commercial drugs in market altogether do not provide complete treatment for neuronal degradation however only treats the disease in a symptomatic way. Dopamine transporter (DAT) plays an important role in the termination of neurotransmission by rapid reuptake of dopamine (DA) from the synaptic cleft into presynaptic terminals where it will be degraded by monoamino oxidase. With the blockade of DAT, level of dopamine in synaptic cleft as well as dopaminergic neurotransmission will increase. We have modelled the human DAT based on a drosophila’s DAT X-ray crystal structure, and minimized it in the environment of the lipid bilayer and solvent water. The transporter was validated with known inhibitors downloaded from CHEMbl database, in Auto Dock 4.2 and GOLD 5 docking software. The obtained results correlated positively with the existing experimental results. The binding free energy for DA, according to preexistent experiments, is ΔGexperimental= -7.4 kcal/mol; while ΔGcalculated= -6.4 kcal/mol was obtained through our studies. The binding position of DA, also, coincides with previous literatures: interaction with Phe320, Asp79, Ser149, Ser422, and Thr156 amino acids. Thus, with the results collected, a new model was designed for potential inhibitors approached through de novo and fragment based drug design. Novel selective DAT inhibitors, when alone or in combination with levodopa, may improve the quality of life in patients suffering from Parkinson’s disease.
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