Receptor dynamics in virtual screening: A dihydrofolate reductase case study.

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Publication Type thesis
School or College College of Pharmacy
Department Pharmaceutics & Pharmaceutical Chemistry
Author Roalstad, Shelly M.
Title Receptor dynamics in virtual screening: A dihydrofolate reductase case study.
Date 2007-12
Description The implications of receptor dynamics virtual screening were explored as part of proof of concept study for an interactive docking, molecular dynamics and scoring strategy. The original study was to demonstrate whether or not the iterative process proposed would relax receptor structures that began as apo (without drug) or homology models toward known holo (with drug) coordinates. Due to species differences in the original receptor test systems, the study was refined to a set of well characterized dihydrofolate reductase (DHFR) receptors. Since both apo and holo structures were not available for each DHFR receptor selected, the goal of relaxing an apo structure toward a holo structure was modified. Various complexes of enzymes, ligand and cofactor were constructed to represent intermediates in the catalytic cycle know to adopt distinct conformations, and the new goal was to demonstrate movement toward one of these conformations during molecular dynamics simulations. Additionally, drug resistant E. coli DHFR and human DHFR structures were selected to probe the possible flexibility differences giving rise to enzymatic activity. Traditional molecular dynamics simulations demonstrated correct conformational change for one enzyme cofactor complex after 70 nanoseconds of simulation. Overall, relatively few complexes experienced any conformational change, indicating the need for longer trajectories or more advanced simulation techniques. Flexible regions of the enzyme described in literature were correctly depicted by trajectory analysis. Flexibility differences between bacterial and vertebrate DHFR showed bacterial DHFR to have more localized movements of three flexible loops and vertebrate DHFR more disperse flexibility. Evaluating the free energy of binding by Molecular Mechanics - Poisson Boltzmann Surface Area (MM-PBSA) methods was shown to be more insightful when employed before and after conformational change rather than over an entire trajectory. Ligand binding values generally independent of enzyme activity demonstrated the necessity of considering binding in the context of the catalytic cycle. Traditional molecular dynamics demonstrated the capability of moving a receptor toward a known conformation, through the resolution of conformational change was depended on the amount of trajectory available. Advanced molecular dynamics methods possible capable of expediting conformational change are proposed for future studies.
Type Text
Publisher University of Utah
Subject Drug Receptors; Drugs:
Subject MESH Pharmaceutical Preparations; Computer-Aided Design
Dissertation Institution University of Utah
Dissertation Name MS
Language eng
Relation is Version of Digital reproduction of "Receptor dynamics in virtual screening: A dihydrofolate reductase case study." Spencer S. Eccles Health Sciences Library. Print version of "Receptor dynamics in virtual screening: A dihydrofolate reductase case study." available at J. Willard Marriott Library Special Collection.. RM31.5 2007 .R63.
Rights Management © Shelly M. Roalsta
Format Medium application/pdf
Identifier us-etd2,4
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
ARK ark:/87278/s65d96gc
Setname ir_etd
Date Created 2012-04-23
Date Modified 2012-04-23
ID 193676
Reference URL https://collections.lib.utah.edu/ark:/87278/s65d96gc