Paclitaxel and Cyclostreptin in theTubulin Binding Site Open Access

Abstract

Abstract Paclitaxel and Cyclostreptin in the Tubulin Binding Site By Yutao Yang The development of new anti-cancer drugs is important in these days. In the first two parts, two microtubule stabilizing agents were explored. In part 1 of this thesis, two conformers of paclitaxel, a FDA approved drug, were compared. In part 2, cyclostreptin was explored using different docking algorithms. In the third part, a high potency measles virus inhibitor was explored by searching the protein data bank.

Table of Contents

Table of Contents Part 1. Tubulin bounded PTX conformation: T-Taxol or PTX-NY...1

Introduction...1 Methods and Results...4

C-13 side chain conformational analysis...4 Energy comparisons for full T-Taxol and PTX-NY structures...6 Bridged taxanes K1 and K2...8 Molecular Dynamics (MD) for T-Taxol and PTX-NY in water...11 Docking of T-Taxol and PTX-NY in -tubulin...11

Discussion...12

Relative energies for PTX C-13 side chains...12 Relative energies for full PTX conformations...13 Highly active bridged taxanes...14 Conformational differences between T-Taxol and PTX-NY...16 Molecular dynamics of PTX in water to locate the T-Taxol and PTX-NY conformations...17 β-tubulin binding poses for T-Taxol and PTX-NY conformations...18

Summary and Conclusions...20

Part 2. Docking and Reactivity of Cyclostreptin with tubulin...22

Introduction...22 Methods and Results...25

Autodock blind docking to the microtubule pore...26 Glide flexible ligand docking...27

AutoDock docking with flexible residues...28 Induced fit docking...32

Discussion...37

AutoDock blind docking...37 Glide flexible ligand docking...38 AutoDock flexible residue docking...39 Induced fit docking...45

Summary and Conclusions...50

Part 3. Possible Interactions between Ligand Trifluoromethyl Groups and Proteins...52

Introduction...52 Methods and Results...53 Discussion...53 Summary and Conclusions...56

References.........................................................................................57

List of Tables Table 1. Relative molecular mechanics energies from MMFFs and OPLS-2005 geometry optimized T-Taxol and PTX-NY C-13 side chains with all the torsion angles constrained...4 Table 2. Single point quantum chemical calculations on the OPLS-2005 optimized T-Taxol and PTX-NY C-13 side chains (all torsions constrained) using different methods and basis sets. ^a NY = PTX-NY and T = T-Taxol conformations...6 Table 3. T-Taxol and PTX-NY structures optimized using several molecular mechanics methods with all the torsion angle constrained...7 Table 4. T-Taxol and PTX-NY conformations optimized without constraints using several molecular mechanics methods...7 Table 5. Single point quantum chemical energies for T-Taxol and PTX-NY conformations, produced by optimization with OPLS-2005 followed by MMFFs with all the torsion angles fixed to these conformations...8 Table 6. T-K1 and NY-K2 geometry optimized without constraints using several different force fields...9 Table 7. T-K2 and NY-K2 geometry optimized without constraints using several different force fields...10 Table 8. Single point B3LYP/6-31G* quantum chemical energies for K1 and K2 in T-Taxol and PTX-NY conformations optimized with OPLS-2005/MMFFs...10

List of Figures Figure 1-1. Paclitaxel (PTX) structure...1 Figure 1-2. Superposition of PTX-NY (Yellow) and T-Taxol (Cyan)...3 Figure 1-3. The C-13 side chain structure...4 Figure 1-4. K1 and K2 structures...9 Figure 1-5. T-Taxol side chain conformer...16 Figure 1-6. PTX-NY side chain conformer...17 Figure 2-1. Mechanism for nucleophilic attack on cyclostreptin...25 Figure 2-2: Structure of cyclostreptin. (a) Reference structure. (b) Structure built and optimized in Maestro8.0.308¹...25 Figure 2-3. Cluster of docking poses from AutoDock Blind Docking. Look from the interior of the microtubule...27 Figure 2-4. One of the docked poses in the PTX binding site using AutoDock4 flexible residue docking is illustrated. The distance between C2 on cyclostreptin and the side chain oxygen on Asp226 is 3.6 Å...29 Figure 2-5. One of the docked poses in the PTX binding site using AutoDock4 flexible residue docking is illustrated. The distance between C2 on cyclostreptin and the pyridine-like nitrogen on His229 is 5.2 Å...30 Figure 2-6. One of the docked poses in the pore area using AutoDock4 flexible residue docking is illustrated. The distance between C2 on cyclostreptin and the oxygen on Thr221 is 3.5 Å, and the distance between C2 on cyclostreptin and the oxygen on Thr220 is 6.2 Å...31 Figure 2-7. One of the docked poses in the PTX binding site using Induced Fit Docking is illustrated. The distance between the C2 on cyclostreptin and the pyridine-like nitrogen on His229 is 4.0 Å...33 Figure 2-8. One of the docked poses in the PTX binding site using Induced Fit Docking is illustrated. This pose shows several hydrogen bonds between cyclostreptin and other residues...34 Figure 2-9. One of the docked poses in the GDP binding site using Induced Fit Docking is illustrated. The distance between the C2 on cyclostreptin and the nitrogen on Asn228 is 6.2 Å, which is the nearest distance between these two atoms...35

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School	Laney Graduate School
Department	Chemistry
Degree	MS
Submission	Dissertation
Language	English
Research Field	Chemistry, Biochemistry Chemistry, General Chemistry, Physical
Keyword	Paclitaxel Molecular Dynamics Quantum Chemistry Docking Force Field Cyclostreptin
Committee Chair / Thesis Advisor	Snyder, James P, Emory University Liotta, Dennis C, Emory University
Committee Members	Lian, Tim, Emory University Lynn, David, Emory University

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