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  

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Control Number  

joongbu:644005