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Discovery and Development of Novel Anti-Infective and Anti-Diabetic Agents- [electronic resource]
Discovery and Development of Novel Anti-Infective and Anti-Diabetic Agents- [electronic resource]
상세정보
- 자료유형
- 학위논문
- Control Number
- 0016930914
- International Standard Book Number
- 9798379785352
- Dewey Decimal Classification Number
- 540
- Main Entry-Personal Name
- Chheda, Pratik Rajesh.
- Publication, Distribution, etc. (Imprint
- [S.l.] : The University of Iowa., 2020
- Publication, Distribution, etc. (Imprint
- Ann Arbor : ProQuest Dissertations & Theses, 2020
- Physical Description
- 1 online resource(191 p.)
- General Note
- Source: Dissertations Abstracts International, Volume: 85-01, Section: B.
- General Note
- Advisor: Kerns, Robert J.
- Dissertation Note
- Thesis (Ph.D.)--The University of Iowa, 2020.
- Restrictions on Access Note
- This item must not be sold to any third party vendors.
- Summary, Etc.
- 요약Drug discovery and development for any disease is a long process involving several key steps like hit identification, lead identification, and lead optimization. Screening a large set of molecules against a specific drug target is the most common method to identify new hit compounds, followed by employing medicinal chemistry principles to perform hit to lead identification. The aim of my thesis research was the successful application of various medicinal, synthetic, and computational chemistry strategies for the identification and development of novel hit and lead molecules for the management of different diseases. In the first project, inhibitors of apicoplast DNA polymerase, which is an antimalarial drug target, were identified and optimized. Screening a small set of compounds followed by performing various enzymatic, crystallographic, and computational studies, revealed the putative mechanism by which new compounds inhibit the function of apPOL. The result of this study is identification of promising hit molecules that can be further optimized to inhibit apPOL more potently and thus can be developed as novel means for the management of malaria. In the second project, guided by computational docking studies and medicinal chemistry, a previously identified hit was optimized, and probes designed to better understand their mechanism of action causing improved insulin secretion and sensitivity. Our studies indicate that in the setting of type-2 diabetes, SWELL1, a key protein involved in insulin signaling, undergoes degradation. Our compounds improve insulin signaling by rescuing SWELL1 protein degradation. Our findings provide detailed understanding of how SWELL1 modulators function and highlight their potential application as novel therapeutics for the management of Type-2-diabetes. H.pylori glutamate racemase is an essential but highly flexible bacterial protein. Due to its high flexibility, application of traditional virtual screening methods is challenging making identification of new inhibitors difficult. In the third project, a hybrid molecular dynamics based virtual docking protocol was developed to identify new hit compounds against H.pylori glutamate racemase. Using the developed protocol, several new hits that inhibit HpGR were identified along with uncovering the mechanism of action of these allosteric inhibitors. Our new understanding of HpGR will aid in the development of selective antibiotics to treat H. pylori infections.
- Subject Added Entry-Topical Term
- Pharmaceutical sciences.
- Subject Added Entry-Topical Term
- Chemistry.
- Subject Added Entry-Topical Term
- Computational chemistry.
- Subject Added Entry-Topical Term
- Biochemistry.
- Index Term-Uncontrolled
- Anti-diabetic
- Index Term-Uncontrolled
- Anti-malarial
- Index Term-Uncontrolled
- Chemical biology
- Index Term-Uncontrolled
- Drug discovery
- Index Term-Uncontrolled
- Virtual screening
- Added Entry-Corporate Name
- The University of Iowa Pharmaceutical Sciences and Experimental Therapeutics
- Host Item Entry
- Dissertations Abstracts International. 85-01B.
- Host Item Entry
- Dissertation Abstract International
- Electronic Location and Access
- 로그인을 한후 보실 수 있는 자료입니다.
- Control Number
- joongbu:644005
MARC
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■1001 ▼aChheda, Pratik Rajesh.
■24510▼aDiscovery and Development of Novel Anti-Infective and Anti-Diabetic Agents▼h[electronic resource]
■260 ▼a[S.l.]▼bThe University of Iowa. ▼c2020
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2020
■300 ▼a1 online resource(191 p.)
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-01, Section: B.
■500 ▼aAdvisor: Kerns, Robert J.
■5021 ▼aThesis (Ph.D.)--The University of Iowa, 2020.
■506 ▼aThis item must not be sold to any third party vendors.
■520 ▼aDrug discovery and development for any disease is a long process involving several key steps like hit identification, lead identification, and lead optimization. Screening a large set of molecules against a specific drug target is the most common method to identify new hit compounds, followed by employing medicinal chemistry principles to perform hit to lead identification. The aim of my thesis research was the successful application of various medicinal, synthetic, and computational chemistry strategies for the identification and development of novel hit and lead molecules for the management of different diseases. In the first project, inhibitors of apicoplast DNA polymerase, which is an antimalarial drug target, were identified and optimized. Screening a small set of compounds followed by performing various enzymatic, crystallographic, and computational studies, revealed the putative mechanism by which new compounds inhibit the function of apPOL. The result of this study is identification of promising hit molecules that can be further optimized to inhibit apPOL more potently and thus can be developed as novel means for the management of malaria. In the second project, guided by computational docking studies and medicinal chemistry, a previously identified hit was optimized, and probes designed to better understand their mechanism of action causing improved insulin secretion and sensitivity. Our studies indicate that in the setting of type-2 diabetes, SWELL1, a key protein involved in insulin signaling, undergoes degradation. Our compounds improve insulin signaling by rescuing SWELL1 protein degradation. Our findings provide detailed understanding of how SWELL1 modulators function and highlight their potential application as novel therapeutics for the management of Type-2-diabetes. H.pylori glutamate racemase is an essential but highly flexible bacterial protein. Due to its high flexibility, application of traditional virtual screening methods is challenging making identification of new inhibitors difficult. In the third project, a hybrid molecular dynamics based virtual docking protocol was developed to identify new hit compounds against H.pylori glutamate racemase. Using the developed protocol, several new hits that inhibit HpGR were identified along with uncovering the mechanism of action of these allosteric inhibitors. Our new understanding of HpGR will aid in the development of selective antibiotics to treat H. pylori infections.
■590 ▼aSchool code: 0096.
■650 4▼aPharmaceutical sciences.
■650 4▼aChemistry.
■650 4▼aComputational chemistry.
■650 4▼aBiochemistry.
■653 ▼aAnti-diabetic
■653 ▼aAnti-malarial
■653 ▼aChemical biology
■653 ▼aDrug discovery
■653 ▼aVirtual screening
■690 ▼a0572
■690 ▼a0485
■690 ▼a0219
■690 ▼a0487
■71020▼aThe University of Iowa▼bPharmaceutical Sciences and Experimental Therapeutics.
■7730 ▼tDissertations Abstracts International▼g85-01B.
■773 ▼tDissertation Abstract International
■790 ▼a0096
■791 ▼aPh.D.
■792 ▼a2020
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T16930914▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a202402▼f2024
