Profiling the structural determinants of aminoketone derivatives as hNET and hDAT reuptake inhibitors by field-based QSAR based on molecular docking

Abstract

BACKGROUND: Bupropion, one of the dual norepinephrine and dopamine reuptake inhibitors (NDRIs), is an aminoketone derivative performed effect in improving cognitive function for depression. However, its therapeutic effect is unsatisfactory due to poor clinical response, and there are only few derivatives in pre-clinical settings. OBJECTIVE: This work attempted to elucidate the essential structural features for the activity and designed a series of novel derivatives with good inhibitive ability, pharmacokinetic and medicinal chemistry properties. METHODS: The field-based QSAR of aminoketone derivatives of two targets were established based on docking poses, and the essential structural properties for designing novel compounds were supplied by comparing contour maps. RESULTS: The selected two models performed good predictability and reliability with R2 of 0.8479 and 0.8040 for training set, Q2 of 0.7352 and 0.6266 for test set respectively, and the designed 29 novel derivatives performed no less than the highest active compound with good ADME/T pharmacokinetic properties and medicinal chemistry friendliness. CONCLUSIONS: Bulky groups in R1, bulky groups with weak hydrophobicity in R3, and potent hydrophobic substituted group with electronegative in R2 from contour maps provided important insights for assessing and designing 29 novel NDRIs, which were considered as candidates for cognitive dysfunction with depression or other related neurodegenerative disorders.

Overlap and Specificity in the Substrate Spectra of Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3

“…While inhibitors of MATs—as well as OCTs—have been studied intensively [ 23 , 24 , 25 , 26 , 27 ] and ligand- as well as structure-based determinants of inhibition have been identified [ 28 , 29 , 30 , 31 ], less is known about the substrate spectra of MATs and OCTs. Especially with MATs, relatively little data is available beyond the narrow substrate group of the neurotransmitters themselves.…”

A multiple-step screening protocol to identify norepinephrine and dopamine reuptake inhibitors for depression

“…In the last part, similarity analysis was performed between NDRI virtual hits and reported compounds by Tanimoto similarity searching. The similarities of compounds to at least one reported NDRI inhibitor in the testing set were calculated by the Tanimoto similarity coefficient as follows: 2,24 where l denotes the number of molecular fingerprints. Two compounds were considered to be similar with a coefficient greater than 0.8, and NDRIs with threshold values lower than this were defined as novel candidates.…”

“…Because there are no crystal structures of hNET and hDAT reported in the Protein Data Bank (PDB), their 3-dimensional (3D) structures were constructed by homology modeling in the SWISS-MODEL workspace 31 as described in our previous work. 2 The stereochemical qualities of obtained homology models were further evaluated by Ramachandran plot analysis in PROCHECK. 18 A docking program was executed in Maestro.…”

“…12,14,15 In the PFC, there is greater distribution of the human norepinephrine transporter (hNET) as compared to the human dopamine transporter (hDAT), while this situation is the opposite in the striatum and NAc. 2,16,17…”

“…Depression is one of the most common mental disorders, and because it is currently experienced by more than 350 million people worldwide, the World Health Organization predictions indicate that it will be the leading global disease burden by 2030. 1,2 It was noted that the number affected might directly and indirectly increase under the influence of the current COVID-19 pandemic. 1 Cognitive dysfunction, a core complication of depression, occurs throughout depressive episodes and may persist even after remission of mood symptoms.…”