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Metoclopramide as a small molecule of dopamine D2 receptor

In Silico Study of Metoclopramide

 Metoclopramide as a small molecule of dopamine D2 receptor

Dopamine D2 receptor (D2R) has been constructed from various natural amino acids in humans that is encoded by DRD2 gene. This protein (D2R) is the most important receptor for many antipsychotic medicines. The D2R structure has been known using a radiolabeled antipsychotic compound. The main agonists for dopamine D2 receptor are bromocriptine, cabergoline, dihydrexidine, piribedil, pramipexole, quinelorane, quinpirole, ropinirole, sumanirole and talipexole. Some drugs like aplindore, aripiprazole, armodafinil, brexpiprazole, cariprazine, ketamine, GSK-789, 2-phenethylamine, LSD, OSU-6162, roxindole, RP5063 and salvinorin A show the partial agonistic activity in interaction with D2R binding sites. In recent years, antagonist drugs have shown better properties than agonist compounds for binding with dopamine D2 receptor. The main antagonist drugs are atypical antipsychotics, cinnarizine, chloroethylnorapomorphine, desmethoxyfallypride, domperidone, metoclopramide, eticlopride, fallypride, hydroxyzine and itopride.

۲-methoxy-4-amino-5-chloro-N,N-(dimethylaminoethyl)benzamide, also known as metoclopramide, is a dopamine D2 antagonist that is used mostly for esophageal and stomach problems. For the first time in 1964, Louis Justin-Besancon introduced metoclopramide. This antagonist drug can bind to dopamine D2 receptor (D2R) with affinity 28.8 nM. Patients with gastroesophageal reflux disease (GERD) use this medicine to relieve heartburn and the esophagus ulcers healing. The other usages of metoclopramide include treatment of vomiting and nausea to help patients with delayed stomach emptying (DSE). Also, it significantly increases the levodopa absorption and plasma levels in man. The injection of metoclopramide is used to treat severe diabetic gastroparesis. On the other hand, the combination of this medicine with aspirin or acetaminophen can be used in the migraine headaches. Metoclopramide has some side effects like feeling restless, depression, diarrhea, movement disorder and feeling tired. Patients containing parkinson’s disease (PD), restless legs syndrome (RLS), ADHD and hyperprolactinaemia should be monitored when using this medicine for emesis treatment.

In 2020, Dr. Mehdi Nabati and his coworkers studied the molecular structure, bonds nature, stability, reactivity and electronic properties of the title molecule. The molecular optimization and all theoretical computations were carried out by density functional theory (DFT) method using the hybrid B3LYP (Becke, three-parameter, Lee-Yang-Parr) exchange-correlation functional employing the 6-31G(d,p) basis set of theory. Quantum-mechanical (QM) computations of the molecular structure geometry of the molecule under study were calculated with scaled quantum mechanics. The global reactivity descriptors like energy gap (Eg), ionization potential (IP), electron affinity (EA), chemical hardness (η), chemical softness (S), electronegativity (χ), electronic chemical potential (μ) and electrophilicity index (ω) can be obtained from the energies of the frontier molecular orbitals (HOMO and LUMO). The calculated global reactivity indices indicated that metoclopramide which was a stable small molecule can bind with the residues of the dopamine D2 receptor (D2R). Molecular docking studies showed that the steric interactions of the ligand with the residues Phe 198, Phe 382, Ala 122, Thr 119, Ser 197, Trp 386, Phe 390, Val 115, Cys 118 and Asp 114 from the protein binding site are the main binding modes between the ligand and the receptor.

For more information about Metoclopramide as a small molecule of dopamine D2 receptor, please read the following article:

In Silico Study of Metoclopramide as A Small Molecule of Dopamine D2 Receptor: a Quantum-Mechanical (QM) Based Molecular Docking Treatment

حتما ببینید

Doctor Mehdi Nabati

Dr. Mehdi Nabati

*************************************** Mehdi Nabati Ph.D. of Organic Chemistry Date of Birth: 22/04/1988 Place of Birth: Maragheh, …

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