Computation-guided analysis of paroxetine binding to hSERT reveals functionally important structural elements and dynamics.

In this study, by carrying out and analyzing the results of extensive and comparative molecular dynamics simulations while also re-evaluating the transport and binding properties of the thermostabilized constructs, we identified functionally important structural elements that are perturbed by these mutations, revealed unexpected dynamics in the central primary binding site of SERT, and uncovered a conceivable ambiguity in paroxetine's binding orientation. We propose that the favored entropy contribution plays a significant role in paroxetine's extraordinarily high affinity for SERT. Our findings lay the foundation for future mechanistic studies and rational design of high-affinity SERT inhibitors. PMID: 30391505 [PubMed - as supplied by publisher]
Source: Neuropharmacology - Category: Drugs & Pharmacology Authors: Tags: Neuropharmacology Source Type: research