Novel Feature Extraction Technique for Fuzzy Relational Clustering of a Flexible Dopamine Reuptake Inhibitor

Abstract

This paper describes a novel clustering methodology for classifying over 700 conformations of a flexible analogue of GBR 12909, a dopamine reuptake inhibitor that has completed phase I clinical trials as a treatment for cocaine abuse. The major aspect of the clustering methodology includes an efficient data-conditioning scheme where a systematic feature extraction procedure based on the structural properties of the molecule was used to reduce the associated feature space. This allowed region-specific clustering that focused on individual pharmacophore elements of the molecule. For clustering of the reduced feature set, the fuzzy clustering partitional method was utilized. Due to the relational nature of the feature data, fuzzy relational clustering was employed, and it successfully detected natural groups defined by rotational minima around N(sp(3))-C(sp(3)), O(sp(3))-C(sp(3)), and C(sp(3))-C(sp(2)) bonds. The proposed clustering methodology also employed several cluster validity measures, which corroborated the partitions produced by the clustering technique and agreed with the results of hierarchical clustering using the XCluster program. Representative structures which exhibited a reasonable spread of energies and showed good spatial coverage of the conformational space were identified for use as putative bioactive conformations in a future Comparative Molecular Field Analysis of GBR 12909 analogues. The clustering methodology developed here is capable of handling other computational chemistry problems, and the feature extraction technique can be easily generalized to other molecules.

Hierarchical clustering analysis of flexible GBR 12909 dialkyl piperazine and piperidine analogs

“…The results of this study are supported by a fuzzy relational clustering (FRC) study performed by Venanzi and coworkers [59]. The FRC study was carried out only on the data set of conformers of 2.…”

“…The detailed protocol for the random search conformational analysis of 2 has been published elsewhere [59]. Briefly, the random search procedure randomly alters the eight torsional angles, then performs a geometry optimization (i.e.…”

Singular value decomposition of torsional angles of analogs of the dopamine reuptake inhibitor GBR 12909

“…Both analogs were protonated on the nitrogen proximal to the A‐side for several reasons: (1) binding studies of piperidine analogs of 1 showed that only this nitrogen was required for activity at the DAT,38 (2) HF/6‐31G* molecular orbital calculations performed on 1 showed that protonation of the nitrogen proximal to the A‐side is favored over that on the B‐side,65 and (3) dopamine66 and cocaine12 are believed to bind to the DAT in the protonated state. The detailed protocol for the random search conformational analysis of 2 has been published elsewhere 60. The same protocol was repeated for 3 .…”

“…Hierarchical58 and fuzzy59 clustering are possible approaches. In separate publications60, 61 we investigate the application of clustering techniques to the classification of conformers of GBR 12909 analogs. In the present work we explore the utility of a complementary technique, singular value decomposition (SVD), to group conformations of GBR 12909 analogs based on the similarity of their nonring torsional angles.…”

Pharmacological Characterization of Novel Opioid Receptor Ligands Aimed at Reducing the Development of Tolerance

“…This concept allows for the design of opioid receptor subtype specific ligands, the δ-selective antagonist naltrindole one of the first. Naltrindole incorporates an indole functional group fused to the "C" ring of the (162)(163)(164). CSP models for µ receptor ligands employ the aromatic "A" ring, basic nitrogen, N-substituent and the "C" ring hydrophobic substituent as the respective pharmacophoric descriptors; these functional groups are deemed the most significant for efficacy at the µ receptor (161).…”