Graduation Year


Document Type




Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Yu Chen, Ph.D.

Committee Member

Robert Deschenes, Ph.D.

Committee Member

Wayne Guida, Ph.D.

Committee Member

Gloria Ferreira, Ph.D.

Committee Member

John Chodera, Ph.D.


chemokines, lipid a biosynthesis, molecular docking, X-ray Crystallography, temocillin, ticarcillin, beta lactamase, penicillin binding protein


Current research in pharmaceutical development commonly utilizes a profusion of methods in molecular modeling in order to probe intricate biological problems. Many original and promising compounds have been identified and developed by integrating experimental and computational methods. Structural biology utilizes many different research techniques including x-ray crystallography, NMR, and electron microscopy in order to develop molecular models of macromolecules that are of biological interest. Such techniques can be used in conjunction with molecular docking, which utilizes those molecular models in order to target macromolecules of therapeutic interest by computationally analyzing the conformations adopted by ligands upon interaction with a desired binding site and estimating the free energy of binding. This technique allows for the screening of millions of compounds with great variety in terms of structure and chemotype. The initial hits of such drug discovery efforts generally consist of low affinity small molecules, but by developing complex structures of these compounds with the macromolecular target they can be optimized through the addition of functional groups and enlarging the compound structure in order to take advantage of the chemical space surrounding the inhibitor within the binding site, which leads to higher affinity compounds. This is the process of a structure based drug design effort and the work herein utilizes this process in order to develop and optimize small molecule inhibitors that offer the potential to be utilized in battling bacterial resistance to current antibiotics and preventing the metastasis of different cancers.