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Abstract
This thesis describes theoretical and computational efforts to quantify the relationship between the P/CAF Bromodomain (Brd), and selective small molecule inhibitors. The goal of this work is further progress in the development of a selective inhibitor of the interaction between the HIV-1 Tat protein and the P/CAF Brd. Specifically, this thesis addresses target flexibility in drug design, the design of selective ligands targeting a conserved domain, and evaluation of the thermodynamic signatures of the ligands of the P/CAF Brd.
To address target flexibility, we develop a small molecule docking method based on mean field theory. We show that this docking method reliably predicts low-energy docked poses with low heavy atom positional root mean squared deviation (RMSD) to a reference structures. We further show that this method identifies low-energy low-RMSD docked poses when structural decoys of our target are used. This is a significant achievement as it addresses problems of identifying the bound conformation, as well as flexibility.
This thesis presents work toward quantifying the translational entropy component of ligand binding. We show that the free volume theory provides consistent results in both Monte-Carlo and molecular dynamics simulations. We also show that the translational component of a series of para-substituted benzamidine ligands to trypsin is relatively invariant relative to the total entropy change on ligand binding.
The work presented here on selectivity in drug design focuses on the structural and sequential similarity of the bromodomain family of proteins. We identify the NP2 P/CAF Brd ligand as having the most selective binding site interactions. We note that the BAZ2A bromodomain has the greatest binding site similarity. We propose that the optimization of the interaction between NP2 and P/CAF residue E42 will create ligands that differentially bind P/CAF.