Development of computational tools to model molecular interactions for medicinal chemistry

Ford, Melissa Coates, author
Ho, P. Shing, advisor
Cohen, Robert, committee member
Snow, Christopher, committee member
McCullagh, Martin, committee member
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Medicinal chemistry has evolved over the past 40 years to rely heavily on the computationally aided design of new drugs. The work in this dissertation focuses on developing computational tools for the application of medicinal chemistry. For computational techniques to be dependable, important interactions must be properly modeled and the techniques must be rigorously tested. In this work, I first introduce an important interaction for drug design, the halogen bond (X-bond). We consider how decades of work has come closer to properly modeling the X-bond, yet there remain many unexplored areas. Two areas are addressed in this dissertation: the structure-energy relationship of 1) a Br…S- X-bond in a DNA junction and 2) Br…O and I…O X-bonds in T4 Lysozyme (T4-L). Using these systems, we can better understand the X-bond and further test computational tools. One such tool, a molecular mechanics/dynamics package, TINKER, does not model X-bonds. Thus, I then incorporate a force field for a broad range of X-bonding molecules into TINKER, creating X-TINKER. X-TINKER reproduces the energies and geometries of the X-bond in the DNA and T4-L systems. Last, I will discuss testing a different software developed by Schrödinger, FEP+. We find FEP+ can effectively predict protein stability; however, it still has areas that need improvement. Together, the findings of this dissertation emphasize the importance of understanding molecular interactions, improving algorithms, and testing current programs to find remaining failures. By continuing to use this cycle, we hope to see the impact of computational tools in medicinal chemistry.
2017 Summer.
Includes bibliographical references.
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molecular mechanics
computational chemistry
halogen bonds
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