NJIT eTD::njit-etd2002-004::Gilbert, Kathleen Mary::"Comparative molecular field analysis (CoMFA) of protonated methylphenidate phenyl-substituted analogs"

Protonated methylphenidate (pMP) and several phenyl-substituted pMP analogs were analyzed using Comparative Molecular Field Analysis (CoMFA) to develop a pharmacophore for dopamine transporter (DAT) binding. This research is a part of an interdisciplinary study on using methylphenidate (MP) analogs to block the binding of cocaine to the DAT as a treatment for addiction.

A random search conformational analysis using key pMP torsional angles was performed to create conformer families representing possible bioactive conformations. The lowest energy pMP conformer of each family was used as a template to create phenyl-substituted pMP analogs.

Partial least squares analysis was used to determine the combination of electrostatic and steric cutoffs that yielded the highest predictability (q 2) . q 2 values above 0.5 were achieved for all conformer families. The best model was used to propose a pharmacophore to predict DAT binding affinity. The results were compared to a previous CoMFA study on neutral MP.

Title:	Comparative molecular field analysis (CoMFA) of protonated methylphenidate phenyl-substituted analogs
Author:	Gilbert, Kathleen Mary
Document Type:	Thesis
Department:	Federated Biological Sciences Department of NJIT and Rutgers-Newark
Degree:	Master of Science
Major:	Computational Biology
Advisory Committee:	Venanzi, Carol A. Recce, Michael Gund, Tamara M.
Thesis Date:	2002, January
Keywords:	Comparative molecular field analysis (CoMFA) Pronated methylphenidate (pMP) Dopamine transporter (DAT) binding
Availability:	Unrestricted
Abstract:	Protonated methylphenidate (pMP) and several phenyl-substituted pMP analogs were analyzed using Comparative Molecular Field Analysis (CoMFA) to develop a pharmacophore for dopamine transporter (DAT) binding. This research is a part of an interdisciplinary study on using methylphenidate (MP) analogs to block the binding of cocaine to the DAT as a treatment for addiction. A random search conformational analysis using key pMP torsional angles was performed to create conformer families representing possible bioactive conformations. The lowest energy pMP conformer of each family was used as a template to create phenyl-substituted pMP analogs. Partial least squares analysis was used to determine the combination of electrostatic and steric cutoffs that yielded the highest predictability (q 2) . q 2 values above 0.5 were achieved for all conformer families. The best model was used to propose a pharmacophore to predict DAT binding affinity. The results were compared to a previous CoMFA study on neutral MP.
Complete Thesis:	njit-etd2002-004 (76 pages ~ 2,924 KB pdf)
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