DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods

Abstract

The dopamine reuptake inhibitor GBR 12909 (1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine, 1) and its analogs have been developed as tools to test the hypothesis that selective dopamine transporter (DAT) inhibitors will be useful therapeutics for cocaine addiction. This 3D-QSAR study focuses on the effect of substitutions in the phenylpropyl region of 1. CoMFA and CoMSIA techniques were used to determine a predictive and stable model for the DAT/serotonin transporter (SERT) selectivity (represented by pK i (DAT/SERT)) of a set of flexible analogs of 1, most of which have eight rotatable bonds. In the absence of a rigid analog to use as a 3D-QSAR template, six conformational families of analogs were constructed from six pairs of piperazine and piperidine template conformers identified by hierarchical clustering as representative molecular conformations. Three models stable to y-value scrambling were identified after a comprehensive CoMFA and CoMSIA survey with Region Focusing. Test set correlation validation led to an acceptable model, with q 2 = 0.508, standard error of prediction = 0.601, two components, r 2 = 0.685, standard error of estimate = 0.481, F value = 39, percent steric contribution = 65, and percent electrostatic contribution = 35. A CoMFA contour map identified areas of the molecule that affect pK i (DAT/SERT). This work outlines a protocol for deriving a stable and predictive model of the biological activity of a set of very flexible molecules.

Studies of New Fused Benzazepine as Selective Dopamine D3 Receptor Antagonists Using 3D-QSAR, Molecular Docking and Molecular Dynamics

“…As seen from Table 3 , in almost all cases the Q 2 scrambling values are slightly lower than the Q 2 values. This is reasonable because Q 2 scrambling values are known to be more conservative than those of LOO/CV PLS Q 2 ones [ 27 ]. And the calculated cross-validated standard deviations of error of prediction (CSDEP) are slightly larger than the SEP values.…”

Feature Extraction Using Molecular Planes for Fuzzy Relational Clustering of a Flexible Dopamine Reuptake Inhibitor

“…The most stable and predictive model was used to successfully interpret the DAT/SERT selectivity of the analogues. 16 This demonstrates that, for flexible molecules, using representative conformers from individual clusters as templates for CoMFA can result in a useful 3D-QSAR model.…”

“…16 This class of dopamine reuptake inhibitors appears to be potentially useful in the treatment of cocaine abuse. 17 GBR 12909 effectively reduced cocaine self-administration in rhesus monkeys 18 and has completed Phase I clinical trials.…”

Recent Advances in Ligand-Based Drug Design: Relevance and Utility of the Conformationally Sampled Pharmacophore Approach

“…The CSP method has also been applied and discussed by other researchers in the context of 3D QSAR [137-145]. CSP models developed by Bernard and coworkers, demonstrated the importance of including extensive conformational sampling in model development.…”

“…This motivated other researchers to include conformational sampling during the development of 3D QSAR models for other flexible systems. Gilbert and coworkers applied the concept of CSP method in their work by considering a set of representative conformations of the flexible ligands to develop selective inhibitors of DAT/SERT using CoMFA and CoMSIA methods [137]. Mallik and coworkers [140] used the CSP method for developing 3D pharmacophore for the 13-residue cyclic peptide, compstatin, an anti-complement peptide and other related peptidic analogues.…”