J Chem Inf Model - Identification of novel serotonin transporter compounds by virtual screening.

Tópicos

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Resumo

The serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) plays an essential role in the termination of serotonergic neurotransmission by removing 5-HT from the synaptic cleft into the presynaptic neuron. It is also of pharmacological importance being targeted by antidepressants and psychostimulant drugs. Here, five commercial databases containing approximately 3.24 million drug-like compounds have been screened using a combination of two-dimensional (2D) fingerprint-based and three-dimensional (3D) pharmacophore-based screening and flexible docking into multiple conformations of the binding pocket detected in an outward-open SERT homology model. Following virtual screening (VS), selected compounds were evaluated using in vitro screening and full binding assays and an in silico hit-to-lead (H2L) screening was performed to obtain analogues of the identified compounds. Using this multistep VS/H2L approach, 74 active compounds, 46 of which had K(i) values of =1000 nM, belonging to 16 structural classes, have been identified, and multiple compounds share no structural resemblance with known SERT binders.

Resumo Limpo

serotonin hydroxytryptamin ht transport sert play essenti role termin serotonerg neurotransmiss remov ht synapt cleft presynapt neuron also pharmacolog import target antidepress psychostimul drug five commerci databas contain approxim million druglik compound screen use combin twodimension d fingerprintbas threedimension d pharmacophorebas screen flexibl dock multipl conform bind pocket detect outwardopen sert homolog model follow virtual screen vs select compound evalu use vitro screen full bind assay silico hittolead hl screen perform obtain analogu identifi compound use multistep vshl approach activ compound ki valu nm belong structur class identifi multipl compound share structur resembl known sert binder

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