Computational approaches for studying and designing protein/inhibitor complexes and membrane protein variants / Krishna Gajan Vijayendran.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Vijayendran, Krishna Gajan, author.

Contributor:

Saven, Jeffrey G., degree supervisor.

Smith, Amos B., degree supervisor.

Dreyfuss, Gideon, degree committee member.

Radhakrishnan, Ravi, degree committee member.

Sharp, Kim, 1973- degree committee member.

University of Pennsylvania. Department of Genomics and Computational Biology, degree granting institution.

Language:

English

Subjects (All):

Penn dissertations--Genomics and computational biology.

Genomics and computational biology--Penn dissertations.

Local Subjects:

Penn dissertations--Genomics and computational biology.

Genomics and computational biology--Penn dissertations.

Physical Description:

xiv, 190 leaves : illustrations ; 29 cm

Production:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2017.

Summary:

Drug discovery of small-molecule protein inhibitors is a vast enterprise that involves several scientific disciplines (i.e. genomics, cell biology, x-ray crystallography, chemistry, computer science, statistics), with each discipline focusing on a particular aspect of the process. In this thesis, I use computational and experimental approaches to explore the most fundamental aspect of drug discovery: the molecular interactions of small-molecules inhibitors with proteins. In Part I (Chapters I and II), I describe how computational docking approaches can be used to identify structurally diverse molecules that can inhibit multiple protein targets in the brain. I illustrate this approach using the examples of microtubule-stabilizing agents and inhibitors of cyclooxygenase(COX)-I and 5-lipoxygenase (5-LOX). In Part II (Chapters III and IV), I focus on membrane proteins, which are notoriously difficult to work with due to their low natural abundances, low yields for heterologous over expression, and propensities toward aggregation. I describe a general approach for designing water-soluble variants of membrane proteins, for the purpose of developing cell-free, label-free, detergent-free, solution-phase studies of protein structure and small-molecule binding. I illustrate this approach through the design of a water-soluble variant of the membrane protein Smoothened, wsSMO. This wsSMO stands to serve as a first-step towards developing membrane protein analogs of this important signaling protein and drug target.

Notes:

Ph. D. University of Pennsylvania 2017.

Department: Genomics and Computational Biology.

Supervisor: Jeffrey G. Saven; Amos B. Smith.

Includes bibliographical references.

OCLC:

1334941870