東華大學圖書館 |

Computational and Chemical Approaches to drug Repurposing.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Computational and Chemical Approaches to drug Repurposing./
作者:	Li, Xuexin.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2023,
面頁冊數:	71 p.
附註:	Source: Dissertations Abstracts International, Volume: 85-06, Section: B.
Contained By:	Dissertations Abstracts International85-06B.
標題:	Software. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30751078
ISBN:	9798381032468

Computational and Chemical Approaches to drug Repurposing.
Li, Xuexin.

Computational and Chemical Approaches to drug Repurposing. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 71 p.

Source: Dissertations Abstracts International, Volume: 85-06, Section: B.

Thesis (Ph.D.)--Karolinska Institutet (Sweden), 2023.

This item must not be sold to any third party vendors.

Drug repurposing, which entails discovering novel therapeutic applications for already existing drugs, provides numerous benefits compared to conventional drug discovery methods. This strategy can be pursued through two primary approaches: computational and chemical. Computational methods involve the utilization of data mining and bioinformatics techniques to identify potential drug candidates, while chemical approaches involve experimental screens oriented to finding new potential treatments based on existing drugs. Both computational and chemical methods have proven successful in uncovering novel therapeutic uses for established drugs. During my PhD, I participated in several experimental drug repurposing screens based on high-throughput phenotypic approaches. Finally, attracted by the potential of computational drug repurposing pipelines, I decided to contribute and generate a web platform focused on the use of transcriptional signatures to identify potential new treatments for human disease. A summary of these studies follows:In Study I, we utilized the tetracycline repressor (tetR)-regulated mechanism to create a human osteosarcoma cell line (U2OS) with the ability to express TAR DNA-binding protein 43 (TDP-43) upon induction. TDP-43 is a protein known for its association with several neurodegenerative diseases. We implemented a chemical screening with this system as part of our efforts to repurpose approved drugs. While the screening was unsuccessful to identify modulators of TDP-43 toxicity, it revealed compounds capable of inhibiting the doxycyclinedependent TDP-43 expression. Furthermore, a complementary CRISPR/Cas9 screening using the same cell system identified additional regulators of doxycycline-dependent TDP43 expression. This investigation identifies new chemical and genetic modulators of the tetR system and highlights potential limitations of using this system for chemical or genetic screenings in mammalian cells.In Study II, our objective was to reposition compounds that could potentially reduce the toxic effects of a fragment of the Huntingtin (HTT) protein containing a 94 amino acid long glutamine stretch (Htt-Q94), a feature of Huntington's disease (HD). To achieve this, we carried out a high-throughput chemical screening using a varied collection of 1,214 drugs, largely sourced from a drug repurposing library. Through our screening process, we singled out clofazimine, an FDA-approved anti-leprosy drug, as a potential therapeutic candidate. Its effectiveness was validated across several in vitromodels as well as a zebrafish model of polyglutamine (polyQ) toxicity. Employing a combination of computational analysis of transcriptional signatures, molecular modeling, and biochemical assays, we deduced that clofazimine is an agonist for the peroxisome proliferator-activated receptor gamma (PPARγ), a receptor previously suggested to be a viable therapeutic target for HD due to its role in promoting mitochondrial biogenesis. Notably, clofazimine was successful in alleviating the mitochondrial dysfunction triggered by the expression of Htt-Q94. These findings lend substantial support to the potential of clofazimine as a viable candidate for drug repurposing in the treatment of polyQ diseases.In Study III, we explored the molecular mechanism of a previously identified repurposing example, the use of diethyldithiocarbamate-copper complex (CuET), a disulfiram metabolite, for cancer treatment. We found CuET effectively inhibits cancer cell growth by targeting the NPL4 adapter of the p97VCP segregase, leading to translational arrest and stress in tumor cells. CuET also activates ribosomal biogenesis and autophagy in cancer cells, and its cytotoxicity can be enhanced by inhibiting these pathways. Thus, CuET shows promise as a cancer treatment, especially in combination therapies.

ISBN: 9798381032468Subjects--Topical Terms:

619355
Software.

Computational and Chemical Approaches to drug Repurposing.
LDR:05058nmm a2200397 4500 001 2397058
005 20240617111727.5
006 m o d
007 cr#unu||||||||
008 251215s2023 ||||||||||||||||| ||eng d
020 $a 9798381032468
035 $a (MiAaPQ)AAI30751078
035 $a (MiAaPQ)Karolinska_1061648757
035 $a AAI30751078
040 $a MiAaPQ $c MiAaPQ
100 1 $a Li, Xuexin. $3 3766821
245 1 0 $a Computational and Chemical Approaches to drug Repurposing.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2023
300 $a 71 p.
500 $a Source: Dissertations Abstracts International, Volume: 85-06, Section: B.
500 $a Advisor: Fernandez-Capetillo, Oscar;Huhn, Daniela.
502 $a Thesis (Ph.D.)--Karolinska Institutet (Sweden), 2023.
506 $a This item must not be sold to any third party vendors.
520 $a Drug repurposing, which entails discovering novel therapeutic applications for already existing drugs, provides numerous benefits compared to conventional drug discovery methods. This strategy can be pursued through two primary approaches: computational and chemical. Computational methods involve the utilization of data mining and bioinformatics techniques to identify potential drug candidates, while chemical approaches involve experimental screens oriented to finding new potential treatments based on existing drugs. Both computational and chemical methods have proven successful in uncovering novel therapeutic uses for established drugs. During my PhD, I participated in several experimental drug repurposing screens based on high-throughput phenotypic approaches. Finally, attracted by the potential of computational drug repurposing pipelines, I decided to contribute and generate a web platform focused on the use of transcriptional signatures to identify potential new treatments for human disease. A summary of these studies follows:In Study I, we utilized the tetracycline repressor (tetR)-regulated mechanism to create a human osteosarcoma cell line (U2OS) with the ability to express TAR DNA-binding protein 43 (TDP-43) upon induction. TDP-43 is a protein known for its association with several neurodegenerative diseases. We implemented a chemical screening with this system as part of our efforts to repurpose approved drugs. While the screening was unsuccessful to identify modulators of TDP-43 toxicity, it revealed compounds capable of inhibiting the doxycyclinedependent TDP-43 expression. Furthermore, a complementary CRISPR/Cas9 screening using the same cell system identified additional regulators of doxycycline-dependent TDP43 expression. This investigation identifies new chemical and genetic modulators of the tetR system and highlights potential limitations of using this system for chemical or genetic screenings in mammalian cells.In Study II, our objective was to reposition compounds that could potentially reduce the toxic effects of a fragment of the Huntingtin (HTT) protein containing a 94 amino acid long glutamine stretch (Htt-Q94), a feature of Huntington's disease (HD). To achieve this, we carried out a high-throughput chemical screening using a varied collection of 1,214 drugs, largely sourced from a drug repurposing library. Through our screening process, we singled out clofazimine, an FDA-approved anti-leprosy drug, as a potential therapeutic candidate. Its effectiveness was validated across several in vitromodels as well as a zebrafish model of polyglutamine (polyQ) toxicity. Employing a combination of computational analysis of transcriptional signatures, molecular modeling, and biochemical assays, we deduced that clofazimine is an agonist for the peroxisome proliferator-activated receptor gamma (PPARγ), a receptor previously suggested to be a viable therapeutic target for HD due to its role in promoting mitochondrial biogenesis. Notably, clofazimine was successful in alleviating the mitochondrial dysfunction triggered by the expression of Htt-Q94. These findings lend substantial support to the potential of clofazimine as a viable candidate for drug repurposing in the treatment of polyQ diseases.In Study III, we explored the molecular mechanism of a previously identified repurposing example, the use of diethyldithiocarbamate-copper complex (CuET), a disulfiram metabolite, for cancer treatment. We found CuET effectively inhibits cancer cell growth by targeting the NPL4 adapter of the p97VCP segregase, leading to translational arrest and stress in tumor cells. CuET also activates ribosomal biogenesis and autophagy in cancer cells, and its cytotoxicity can be enhanced by inhibiting these pathways. Thus, CuET shows promise as a cancer treatment, especially in combination therapies.
590 $a School code: 0658.
650 4 $a Software. $2 gtt. $3 619355
650 4 $a Toxicity. $3 3564836
650 4 $a Success. $3 518195
650 4 $a Disease. $3 705846
650 4 $a Biosynthesis. $3 516407
650 4 $a Cancer therapies. $3 3557730
650 4 $a Binding sites. $3 3560349
650 4 $a Oncology. $3 751006
650 4 $a Research & development--R&D. $3 3554335
650 4 $a Hepatitis C. $3 834557
650 4 $a Drug resistance. $3 1602664
650 4 $a Cystic fibrosis. $3 820635
650 4 $a Monte Carlo simulation. $3 3564916
650 4 $a Medical research. $2 bicssc $3 1556686
650 4 $a Flexibility. $3 3560705
650 4 $a Biomarkers. $3 2205735
650 4 $a Encyclopedias. $3 531417
650 4 $a Medicine. $3 641104
650 4 $a Pharmaceutical sciences. $3 3173021
650 4 $a Pharmacology. $3 634543
650 4 $a Toxicology. $3 556884
650 4 $a Virology. $3 642304
690 $a 0800
690 $a 0992
690 $a 0564
690 $a 0572
690 $a 0419
690 $a 0383
690 $a 0720
710 2 $a Karolinska Institutet (Sweden). $3 3557748
773 0 $t Dissertations Abstracts International $g 85-06B.
790 $a 0658
791 $a Ph.D.
792 $a 2023
793 $a English
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30751078