Recent advances and challenges of the drugs acting on monoamine transporters

December 13, 2018

Zhu et al. have reviewed the recent developments in the knowledge about the binding, inhibitory mechanisms and structure-activity relationships of hSERT, hNET and hDAT, which are primary human monoamine transporters hMATs. These mechanisms will be used for the future synthesis, design and discovery of hMAT inhibitors for curing depression and behavioral disorders. Researchers will also be able to test these inhibitors in in vitro and in vivo experiments and with the help of computation models.

This review summarizes the structure information, activity and selectivity characteristics, binding modes and side effects of the approved, in clinical studies or developed compounds.

The information will play an important role in the structure-based discovery of novel chemotypes and chemical fragments with high activity and selectivity to the central site related to antidepressants targeting hMATs.

The structure and activity functions, selectivity of human monoamine transporters (hMATs) were determined with the help of studying X-ray crystal structures; in the case of hSERT these crystal structures revealed 5+5 inverted-topological repeats in protein formed by TM1 to TM5 and from TM 6 to TM10. Site mutagenesis experiments and X-ray crystal structures showed that the central binding site of MATs is encircled mainly of residues of TM1, TM3, TM6, TM8 and TM10 and substrates 5-HT, NE and DA bound in the central sit. Antidepressants drugs SSRIs, SNRIs and TRIs lock the transporter in outward-open conformation.

The allosteric binding site of the compounds were established by MD simulation-based MM/GBSA binding free energy calculations. Docking based VS, and pharmacological based VS studies were also reported for the discovery of hSERT inhibitors.

Synthesis, efficacy, inhibition structure activity of sNRIs, sDRIs, SNRIs, SDRIs and TRIs and experimental models were studied in detail and the information has been presented in tabular from for the benefit of the reader. Similarly, the design & synthesis and binding affinity with SERT of dual acting agents were reviewed in this manuscript with help of Computer Aided Drug Design (CADD).

The allosteric inhibitors ATM7 was reported with the help of integrating computational simulation and CADD approached. Several other small molecules were recently identified as hSERT allosteric inhibitors. A new class of novel allosteric modulators of the hNET and hDAT were also reported.

Imaging agents for human MATs in living cells were synthesized. Compound IDT374 revealed the highest potency for interaction with hSERT.

The authors comment that hMAT targeting drugs may be used more increasingly in the future and we may see some more drugs of this type in approved by regulatory authorities in the future.
This article is Open Access. To obtain the article please visit

Bentham Science Publishers

Related Drugs Articles from Brightsurf:

The danger of Z-drugs for dementia patients
Strong sleeping pills known as 'Z-drugs' are linked with an increased risk of falls, fractures and stroke among people with dementia, according to new research.

Wallflowers could lead to new drugs
Plant-derived chemicals called cardenolides - like digitoxin - have long been used to treat heart disease, and have shown potential as cancer therapies.

Bristol pioneers use of VR for designing new drugs
Researchers at the University of Bristol are pioneering the use of virtual reality (VR) as a tool to design the next generation of drug treatments.

Towards better anti-cancer drugs
The Bayreuth biochemist Dr. Claus-D. Kuhn and his research team have deciphered how the important human oncogene CDK8 is activated in cells of healthy individuals.

Separating drugs with MagLev
The composition of suspicious powders that may contain illicit drugs can be analyzed using a quick and simple method called magneto-Archimedes levitation (MagLev), according to a new study published in the journal Angewandte Chemie.

People are more likely to try drugs for the first time during the summer
American teenagers and adults are more likely to try illegal or recreational drugs for the first time in the summer, a new study shows.

Drugs used to enhance sexual experiences, especially in UK
Combining drugs with sex is common regardless of gender or sexual orientation, reveals new research by UCL and the Global Drug Survey into global trends of substance-linked sex.

Promising new drugs for old pathogen Mtb
UConn researchers are targeting a metabolic pathway, the dihydrofolate reductase pathway, crucial for amino acid synthesis to treat TB infections.

Can psychedelic drugs heal?
Many people think of psychedelics as relics from the hippie generation or something taken by ravers and music festival-goers, but they may one day be used to treat disorders ranging from social anxiety to depression, according to research presented at the annual convention of the American Psychological Association.

New uses for existing antiviral drugs
Broad-spectrum antiviral drugs work against a range of viral diseases, but developing them can be costly and time consuming.

Read More: Drugs News and Drugs Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to