A Computational Analysis of Structural Analogs of Colchicineas Potential Microtubule Polymerization Inhibitors
Abstract
Microtubules are structures important for cell survival and cell function. They are responsible for the formation of the cytoskeleton and mitotic spindles, they aid in cell movement, intracellular transport, amongst other functions. Microtubules are composed of the tubulin protein made of alpha-beta dimer proteins. During polymerization tubulin proteins experience phases of dynamic instability, characterized by microtubule growth and shrinkage at varying rates. Microtubule growth can be inhibited by compounds such as colchicine, a known microtubule destabilizing agent, that binds to tubulin inhibiting microtubule polymerization. Colchicine has limited clinical use due to its toxicity and low solubility. In this study we investigated one hundred eleven compounds that had a similar structure to colchicine. We used AutoDock Vina to computationally dock each compound, including colchicine, to tubulin in the same binding site as colchicine. Auto dock was able to replicate the crystal structure of colchicine with a binding energy of -10.9 kcal/mol. Results showed that the binding energies of compounds with the 10% highest binding affinity were between -9 kcal/mol and -7.9 kcal/mol. We also used computational methods to determine that all top 10% drugs have high solubility in comparison to colchicine. The solubility of these drugs and binding affinity to the microtubule indicates the potential of these drugs as inhibitors of microtubule polymerization, which will be further explored through laboratory experiments.
Faculty Sponsors
Dr. Travis J.A. Craddock
Project Type
Event
Location
Alvin Sherman Library
Start Date
4-6-2022 12:00 PM
End Date
4-7-2022 5:00 PM
A Computational Analysis of Structural Analogs of Colchicineas Potential Microtubule Polymerization Inhibitors
Alvin Sherman Library
Microtubules are structures important for cell survival and cell function. They are responsible for the formation of the cytoskeleton and mitotic spindles, they aid in cell movement, intracellular transport, amongst other functions. Microtubules are composed of the tubulin protein made of alpha-beta dimer proteins. During polymerization tubulin proteins experience phases of dynamic instability, characterized by microtubule growth and shrinkage at varying rates. Microtubule growth can be inhibited by compounds such as colchicine, a known microtubule destabilizing agent, that binds to tubulin inhibiting microtubule polymerization. Colchicine has limited clinical use due to its toxicity and low solubility. In this study we investigated one hundred eleven compounds that had a similar structure to colchicine. We used AutoDock Vina to computationally dock each compound, including colchicine, to tubulin in the same binding site as colchicine. Auto dock was able to replicate the crystal structure of colchicine with a binding energy of -10.9 kcal/mol. Results showed that the binding energies of compounds with the 10% highest binding affinity were between -9 kcal/mol and -7.9 kcal/mol. We also used computational methods to determine that all top 10% drugs have high solubility in comparison to colchicine. The solubility of these drugs and binding affinity to the microtubule indicates the potential of these drugs as inhibitors of microtubule polymerization, which will be further explored through laboratory experiments.
