Date of Award

Spring 2004

Document Type

Thesis

Degree Name

Master of Science in Computational Biology - (M.S.)

Department

College of Computing Sciences

First Advisor

Carol A. Venanzi

Second Advisor

Barry Cohen

Third Advisor

Qun Ma

Abstract

Ring substructures of a drug usually participate actively in binding to the receptor. It is necessary to study the spatial relationship of these molecular recognition features in order to determine the pharmacophore of the drug. This is a particularly difficult problem when the drug is a flexible molecule with many energetically accessible conformations.

In this research an innovative approach to calculate the relative displacement and orientation of every possible pair of rings in a given molecule was designed, tested, and implemented in the "Planes" program. Planes were defined from each of the ring substructures and the displacement and rotation of one ring with respect to the other was calculated. This approach was derived from the guidelines of 3DNA, a robust program that calculates base-pair and base-step parameters of nucleic acids. The Planes program was subsequently utilized to analyze the conformations of DM324, a flexible analog of GBR 12909, a drug potentially useful in the treatment of cocaine abuse.

The present work suggests that the Planes program could be potentially useful in the description of the relative orientation of pharmacophore features if the molecular conformations could first be classified by their orientation relative to the central piperazine ring.

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