Recent advances and challenges of the drugs acting on monoamine transporters
This article by Dr. Weiwei Xue et al. is published in Current Medicinal Chemistry, 2019, 26, 1-42
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.
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Faizan ul Haq