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Browsing by Subject "Drug Discovery"
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Item Design, Development and Implementation of Tools in Drug DiscoveryCheemakurthi, Usha Deepika; Forsythe, KelseyThe main focus of our work is to develop, apply and assess cheminformatics tools and methods. In particular, we focus on the following three areas: Integration of open source tools with application to drug discovery, usability studies to assess the efficacy of these software tools and finally, developing novel techniques for database query. Rapid globalization in the present time has sparked a need in the scientific community to interact with each other at an economic and a fast pace. This is achieved by developing and sharing open source databases using World Wide Web. A web based open source database application has been developed to incorporate freeware from varied sources. The deployment of developed database and user interface in a university lab setting is discussed. To aid in connecting the end user and the software tools, usability studies are necessary. These studies communicate the end users’ needs and desires, resulting in a user-friendly and more powerful interactive software packages. Usability studies were conducted on developed database student application and on different drawing packages to determine their effectiveness. Developing new and interactive search engines to query publicly available databases helps researchers work more efficiently. The huge volume of data available and its heterogeneous nature presents issues related to querying, integration and presentation. In aiding the retrieval process, an innovative multi faceted classification system, called ChemFacets, is developed. This system provides dynamic categorization of large result sets retrieved from multiple databases.Item Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy(ACS Publications, 2017-06-08) Rietz, Anne; Li, Hongxia; Quist, Kevin M.; Cherry, Jonathan J.; Lorson, Christian L.; Burnett, Barrington; Kern, Nicholas L.; Calder, Alyssa N.; Fritsche, Melanie; Lusic, Hrvoje; Boaler, Patrick J.; Choi, Sungwoon; Xing, Xuechao; Glicksman, Marcie A.; Cuny, Gregory D.; Androphy, Elliot J.; Hodgetts, Kevin J.; Dermatology, School of MedicineSpinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA.Item Molecular Recognition in a Diverse Set of Protein-Ligand Interactions Studied with Molecular Dynamics Simulations and End-Point Free Energy Calculations(ACS Publications, 2013-10-28) Wang, Bo; Li, Liwei; Hurley, Thomas D.; Meroueh, Samy O.; Department of Biochemistry & Molecular Biology, School of MedicineEnd-point free energy calculations using MM-GBSA and MM-PBSA provide a detailed understanding of molecular recognition in protein-ligand interactions. The binding free energy can be used to rank-order protein-ligand structures in virtual screening for compound or target identification. Here, we carry out free energy calculations for a diverse set of 11 proteins bound to 14 small molecules using extensive explicit-solvent MD simulations. The structure of these complexes was previously solved by crystallography and their binding studied with isothermal titration calorimetry (ITC) data enabling direct comparison to the MM-GBSA and MM-PBSA calculations. Four MM-GBSA and three MM-PBSA calculations reproduced the ITC free energy within 1 kcal•mol−1 highlighting the challenges in reproducing the absolute free energy from end-point free energy calculations. MM-GBSA exhibited better rank-ordering with a Spearman ρ of 0.68 compared to 0.40 for MM-PBSA with dielectric constant (ε = 1). An increase in ε resulted in significantly better rank-ordering for MM-PBSA (ρ = 0.91 for ε = 10). But larger ε significantly reduced the contributions of electrostatics, suggesting that the improvement is due to the non-polar and entropy components, rather than a better representation of the electrostatics. SVRKB scoring function applied to MD snapshots resulted in excellent rank-ordering (ρ = 0.81). Calculations of the configurational entropy using normal mode analysis led to free energies that correlated significantly better to the ITC free energy than the MD-based quasi-harmonic approach, but the computed entropies showed no correlation with the ITC entropy. When the adaptation energy is taken into consideration by running separate simulations for complex, apo and ligand (MM-PBSAADAPT), there is less agreement with the ITC data for the individual free energies, but remarkably good rank-ordering is observed (ρ = 0.89). Interestingly, filtering MD snapshots by pre-scoring protein-ligand complexes with a machine learning-based approach (SVMSP) resulted in a significant improvement in the MM-PBSA results (ε = 1) from ρ = 0.40 to ρ = 0.81. Finally, the non-polar components of MM-GBSA and MM-PBSA, but not the electrostatic components, showed strong correlation to the ITC free energy; the computed entropies did not correlate with the ITC entropy.Item Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion(Elsevier, 2019-07-25) Brewer, M. Kathryn; Uittenbogaard, Annette; Austin, Grant L.; Segvich, Dyann M.; DePaoli-Roach, Anna; Roach, Peter J.; McCarthy, John J.; Simmons, Zoe R.; Brandon, Jason A.; Zhou, Zhengqiu; Zeller, Jill; Young, Lyndsay E. A.; Sun, Ramon C.; Pauly, James R.; Aziz, Nadine M.; Hodges, Bradley L.; McKnight, Tracy R.; Armstrong, Dustin D.; Gentry, Matthew S.; Biochemistry and Molecular Biology, School of Medicine