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Title: Computational Approaches to Explore Druggable Targets of Mycobacterium Tuberculosis and Human Immunodeficiency Virus and Identify Their Potential Inhibitors
Researcher: Chinmayee Choudhury
Guide(s): G. Narahari Sastry and Deva Priyakumar
University: International Institute of Information Technology, Hyderabad
Completed Date: 28/08/2015
Abstract: Rigorous computational approaches at various length and time scales to understand the important druggable targets of MTb and HIV as well as strategies for identifying dual inhibitors of MTb and HIV. Mycobacterial cyclopropane synthase (CmaA1), one of the important drug targets of MTb. Representative models of CmaA1 corresponding to different stages in the cyclopropanation process were studied using molecular dynamics (MD) simulations. Structure and ligand based pharmacophore models were generated using the MD trajectories of the model systems. These performances have been validated by mapping 23 CmaA1 inhibitors and by comparing the pharmacophore mapping scores with the corresponding docking scores. A novel virtual screening approach was employed using these models aiming towards repurposing the existing drugs, also to find compounds that inhibit multiple targets of MTb as well as HIV to inhibit CmaA1. A total of 18,239 compounds were screened against CmaA1 using four levels of screening i.e., ligand based pharmacophore screening, structure based pharmacophore screening, docking and absorption, distribution, metabolism, excretion, toxicity filters. Twelve compounds were identified as potential hits for CmaA1. These compounds were found to interact with the key active site residues of CmaA1. An analogue-based approach was employed to predict the inhibitory activities of compounds against HIV protease. This study critically examines the role of C-DFT descriptors and docking scores along with the other conventional types of descriptors on a diverse set of 156 inhibitors of HIV proteases. A huge number of QSAR models were developed based on available experimental IC50 values. An exhaustive analysis of target binding, ADMET/physicochemical properties of 110 natural products (NP) and NP derivative (ND) drugs reported in DrugBank, containing hexadecahydro-1Hcyclopenta[a]phenanthrene framework (HHCPF) were performed to understand their structural and functional diversities and target specificities.
Appears in Departments:Computational Natural Sciences

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02_certificate.pdf8.78 MBAdobe PDFView/Open
03_acknowledgment.pdf20.89 kBAdobe PDFView/Open
04_abstract.pdf71.98 kBAdobe PDFView/Open
05_contents.pdf20.78 kBAdobe PDFView/Open
06_list of figure and tables.pdf25.95 kBAdobe PDFView/Open
07_list of abbrevations.pdf15.11 kBAdobe PDFView/Open
08_chapter 1.pdf734.16 kBAdobe PDFView/Open
09_chapter 2.pdf543.76 kBAdobe PDFView/Open
10_chapter 3.pdf2.36 MBAdobe PDFView/Open
11_chapter 4.pdf1.42 MBAdobe PDFView/Open
12_chapter 5.pdf1.77 MBAdobe PDFView/Open
13_chapter 6.pdf687.22 kBAdobe PDFView/Open
14_chapter 7.pdf1.35 MBAdobe PDFView/Open
15_chapter 8.pdf240.75 kBAdobe PDFView/Open
16_list of publications.pdf158.01 kBAdobe PDFView/Open

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