Date of Award
Master of Science in Computational Biology - (M.S.)
Federated Department of Biological Sciences
Carol A. Venanzi
Tamara M. Gund
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.
Gilbert, Kathleen Mary, "Comparative molecular field analysis (CoMFA) of protonated methylphenidate phenyl-substituted analogs" (2001). Theses. 673.