東華大學圖書館 |

Language: English

Help

回圖書館首頁

手機版館藏查詢

Back

Switch To: Labeled | MARC Mode | ISBD

Combinatorial library design of muta...

University of Maryland, College Park., Molecular and Cell Biology.

Linked to FindBook

Google Book

Amazon

博客來

Combinatorial library design of mutation-resistant HIV protease inhibitors.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Combinatorial library design of mutation-resistant HIV protease inhibitors./
Author:	Chellappan, Sripriya.
Description:	179 p.
Notes:	Adviser: Michael K. Gilson.
Contained By:	Dissertation Abstracts International68-04B.
Subject:	Biology, Bioinformatics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3260264

Combinatorial library design of mutation-resistant HIV protease inhibitors.
Chellappan, Sripriya.

Combinatorial library design of mutation-resistant HIV protease inhibitors. - 179 p.

Adviser: Michael K. Gilson.

Thesis (Ph.D.)--University of Maryland, College Park, 2007.

The emergence of HIV strains that are resistant to current HIV protease inhibitors in the past few years has become a major concern in AIDS treatment. The goal of this project is to design a combinatorial library of potential lead compounds that can bind to both the wild-type and mutant proteases and that can resist further mutations. A recent crystallographic study of complexes of HIV protease with its substrates has provided structural insights into the differential recognition of the substrates and inhibitors. It has been proposed that clinical resistance is a consequence of inhibitors failure to stay within the consensus substrate volume. In this work, we devised a quantitative indicator of the degree to which a candidate ligand falls outside the consensus substrate volume, and determined its correlation with the inhibitor's sensitivity to clinically relevant resistant mutations. The validation of this hypothesis has encouraged us to use this strategy in our design of a combinatorial library of inhibitors.Subjects--Topical Terms:

1018415
Biology, Bioinformatics.

Combinatorial library design of mutation-resistant HIV protease inhibitors.
LDR:03056nam 2200289 a 45 001 861627
005 20100720
008 100720s2007 ||||||||||||||||| ||eng d
035 $a (UMI)AAI3260264
035 $a AAI3260264
040 $a UMI $c UMI
100 1 $a Chellappan, Sripriya. $3 1029344
245 1 0 $a Combinatorial library design of mutation-resistant HIV protease inhibitors.
300 $a 179 p.
500 $a Adviser: Michael K. Gilson.
500 $a Source: Dissertation Abstracts International, Volume: 68-04, Section: B, page: 2075.
502 $a Thesis (Ph.D.)--University of Maryland, College Park, 2007.
520 $a The emergence of HIV strains that are resistant to current HIV protease inhibitors in the past few years has become a major concern in AIDS treatment. The goal of this project is to design a combinatorial library of potential lead compounds that can bind to both the wild-type and mutant proteases and that can resist further mutations. A recent crystallographic study of complexes of HIV protease with its substrates has provided structural insights into the differential recognition of the substrates and inhibitors. It has been proposed that clinical resistance is a consequence of inhibitors failure to stay within the consensus substrate volume. In this work, we devised a quantitative indicator of the degree to which a candidate ligand falls outside the consensus substrate volume, and determined its correlation with the inhibitor's sensitivity to clinically relevant resistant mutations. The validation of this hypothesis has encouraged us to use this strategy in our design of a combinatorial library of inhibitors.
520 $a The compounds in a typical combinatorial library are built around a common structural scaffold possessing multiple connection points where substituents can be added by reliable synthetic steps. As the number of compounds encompassed by such a combinatorial scheme frequently exceeds what can actually be synthesized and tested, virtual screening methods are sought to shortlist the compounds. Even though these methods require only seconds to minutes of CPU time per compound, exhaustive screening of an entire virtual combinatorial library is computationally demanding. We therefore implemented a simple algorithm of combining substituents that have been optimized independently for the substituent sites. This method was compared with Genetic Algorithm, a global optimization method and was found equally efficient. This simple method was hence chosen for the design process.
520 $a A combinatorial library based on these ideas and methods has been synthesized and tested. It includes four compounds with nanomolar inhibition constants. Two of them were shown to have retained affinity against a panel of treatment-resistant mutations.
590 $a School code: 0117.
650 4 $a Biology, Bioinformatics. $3 1018415
650 4 $a Biology, Molecular. $3 1017719
690 $a 0307
690 $a 0715
710 2 $a University of Maryland, College Park. $b Molecular and Cell Biology. $3 1029343
773 0 $t Dissertation Abstracts International $g 68-04B.
790 $a 0117
790 1 0 $a Gilson, Michael K., $e advisor
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3260264