Browsing by Subject "Drug development"

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    Fragment based inhibitor design of Mycobacterium tuberculosis BioA
    (2015-01) Dai, Ran
    7,8-Diaminopelargonic acid synthase (BioA) of Mycobacterium tuberculosis (Mtb) is a recently validated target for therapeutic intervention in the treatment of tuberculosis (TB). We herein report our fragment based inhibitor design of Mtb BioA. Using differential scanning fluorimetry (DSF) fragment screening, the Maybridge Ro3 library of 1000 molecules was screened. Twenty-one compounds giving rise to Tm shifts exceeding ±2°C were then investigated in crystallographic experiments. Six fragments have been co-crystallized with BioA to characterize binding. Each compound has a unique binding mode, and subtle variations in ligand binding site geometry are induced upon binding of different fragment molecules. Binding affinities of the fragments were characterized via isothermal titration calorimetry (ITC). A fragment extension strategy was used to rationally optimize these fragment hits. A commerce based SAR was used and identified 50 compounds containing the core of one of the fragments. These compounds were further screened virtually and experimently by DSF. Four optimized BioA ligands from fragment optimization were validated by X-ray crystallography, including a potent aryl hydrazine inhibitor of BioA that reversibly modifies the pyridoxal-5′-phosphate (PLP) cofactor. Binding affinities of these ligands have been characterized by ITC or kinetic assay. The six fragment complex structures were also used for optimization of HTS lead compounds. Six HTS lead compounds were co-crystallized with BioA at high resolution. Design of optimized compounds was by overlapping the fragments and HTS lead binding conformations in the BioA active site. Molecules predicted to have better potency were proposed. Two N-aryl piperazine inhibitors of BioA from HTS optimization were characterized using X-ray crystallography and ITC. One inhibitor that combines features of one HTS lead and one fragment was confirmed with improved binding affinity by ITC.
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    Repeated Alliances Across Product Markets: The Formation and Performance Implications
    (2023) Park, Sohyuun
    This dissertation explores a phenomenon of market entry through cross-market repeated alliance, or market entry through repeated alliance with an existing partner from another product market. While it has been studied much how firms use its internal resources to enter a product market, relational resources have received little attention as valuable firm resources in market entry. Such lack of studies on the use of relational resources in market entry is surprising, considering that strategic alliance is an important strategic tool of firms. In this regard, in the first chapter, I examine when firms enter product markets through cross-market repeated alliances with existing partners rather than find new partners. Furthermore, the second chapter studies the performance implications of such cross-market repeated alliances in market entry. I study these questions in the context of the U.S. pharmaceutical industry where there are 15 distinct therapeutic areas. I configure a fine-grained dataset on alliance activities, drug development activities, and patents of firms in the U.S pharmaceutical industry from 1986 to 2019. I find that the cross-market repeated alliance is a salient phenomenon that bears attention. Firms use cross-market repeated alliances in market entry not only to successfully expand their corporate scope, but also to solidify their existing collaborations in other product markets. Cross-market repeated alliance is also a more efficient way to innovate compared to new partner alliance. These findings highlight the importance of relational resources in market entry and extend our understandings on repeated alliances by identifying the product markets of alliances.