Tuberculosis kills approximately 1.7 million people each year around the world making it one of the most lethal infectious diseases. This thesis concerns the development of two computational tools that can support the early stages of drug discovery, and their use in an anti-tubercular drug discovery program. One of the tools developed is a statistical molecular design (SMD) approach that generates information-rich libraries biased towards a lead structure. The other metod is a post-filtering technique to increase the success of virtual screening, has also been developed. Both methods have been validated using literature data. Ribonucleotide reductase (RNR) has been identified as a potential anti-tubercular target, and our focus has been to develop small-molecule inhibitors of this target. The enzyme consists of two subunits (a large R1 and a small R2 subunit) that have to associate in order to generate a bioactive complex. It had previously been shown that a heptapeptide corresponding to the small R2 subunits C-terminal inhibited the enzyme. In order to investigate the requirements for inhibitory effect of the peptide a library was designed using the developed SMD approach. The designed library was synthesized and evaluated for biological activity and an OPLS-DA model was derived to understand which positions were most important for activity. In order to identify small-molecule inhibitors of RNR a combined shape- and structure-based virtual screen was performed, employing ROCS, GlideXP and the developed post-filtering technique. Starting from a library of 1.5 million compounds 24 was acquired and evaluated for enzymatic activity. The best compounds were almost as potent as the starting peptide, but considerably more drug-like.

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This study reports a series of promising and structurally diverse potential HIV-1 protease inhibitors. Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immune Deficiency Syndrome (AIDS). HIV infection disrupts the immune system and makes the body susceptible to opportunistic infections. If untreated, AIDS is generally fatal. Today, AIDS has become a long lasting pandemic. According to the World Health Organization (WHO) and Joint United Nations Program (UNAIDS-2009) report, it is estimated that 33.3 million men, women and children worldwide are infected with HIV. This situation is steadily deteriorating in some parts of the world compared to the previous years. One of the major drawbacks associated with the currently FDA-approved anti-HIV drugs are severe side effects, toxicities, high dosage and high treatment cost. Thus, an urgent need for new drugs to combat HIV is apparent. In the first part of the study, research efforts were focused to synthesize potent pentacycloundecane (PCU) derived peptide and peptoids as protease inhibitors. It is proposed that these inhibitors bind to wild type C-South African HIV protease (C-SA) catalytic site via a non-cleavable or non-hydrolysable cyclic ether bond for the first polycyclic cage compound and via a dihydroxylethelene type functional group for the second cage compound. The desired compounds were synthesized by coupling of the peptides and peptoids to the PCU derived cage. Second part of the study involves, biological evaluation against wild type C-SA enzyme and characterization of the synthesized compounds by Nuclear Magnetic Resonances (NMR). All the synthesized novel compounds were evaluated against wild type C-SA enzyme for their ability to inhibit 50% of the enzyme’s activity (IC50). Some of the compounds reported herein showed promising activity by inhibiting the enzyme activity at concentrations of less than 0.6 nM. 2D NMR investigations employing a new Efficient Adiabatic Symmetrized Rotating Overhauser Effect Spectroscopy (ROESY / NOESY) technique enabled the attainment of vital information about the 3D structure of these small linear peptides and peptoids in solution. The activity could be related to conformations induced by the PCU moiety on the coupled peptide side chain. Further quantum mechanics/molecular mechanics/molecular dynamics (QM/MM/MD) simulations were carried out to confirm the observed NMR experimental results. Docking studies were performed for the synthesized compounds. Binding energies obtained from the docking calculations were then used to further validate the experimental IC50 results. These experimental and theoretical methods provided valuable insight into the interaction mode of these cage peptide and peptoids inhibitors with the enzyme. / Thesis (Ph.D.)-Unversity of KwaZulu-Natal, Westville, 2012.

Thesis (PhD)--University of South Australia, 2004.

Thesis (Ph. D.)--Indiana University, Dept. of Chemistry, 2005. / Title from PDF t.p. (viewed Dec. 8, 2008). Source: Dissertation Abstracts International, Volume: 66-05, Section: B, page: 2595. Chair: Jeffrey N. Johnston.

Thesis (M.S.)--Rowan University, 2005. / Typescript. Includes bibliographical references.

Thesis (Ph.D.)--University of California, San Francisco, 2009. / Source: Dissertation Abstracts International, Volume: 71-02, Section: B, page: . Adviser: Brian K. Shoichet.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1969. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 78-82).

Thesis (Ph. D.)--Syracuse University, 2005. / "Publication number AAT 3194023."

Thesis (Ph. D.)--University of Illinois at Urbana-Champaign, 2006. / Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3813. Adviser: Eric Oldfield. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.