Structure-based design of an inhibitor modeled at the substrate active site of aldose reductase

Giulio Rastelli, Paola Vianello, Daniela Barlocco, Luca Costantino, Antonella Del Corso, Umberto Mura

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

This study presents the first successful example of structure-based drug design on aldose reductase in the extant literature. Starting from the structure of the modeled complex of aldose reductase with a pyridazinone acetic acid inhibitor that we previously disclosed, using the tools of molecular modeling for structure manipulation and molecular mechanics for energy minimization, we were able to design and synthesize a new analog that showed remarkably improved activity. We hope that a proper account of the most important enzyme-inhibitor interactions revealed by this study mill allow, in the future, the design of new lead compounds having structures unrelated to carboxylic acids.

Original languageEnglish
Pages (from-to)1897-1902
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume7
Issue number14
DOIs
Publication statusPublished - Jul 22 1997

Fingerprint

Aldehyde Reductase
Catalytic Domain
Drug Design
Enzyme Inhibitors
Substrates
Carboxylic Acids
Molecular Structure
Mechanics
Acetic Acid
Lead compounds
Molecular mechanics
Molecular modeling
Pharmaceutical Preparations
Lead

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Structure-based design of an inhibitor modeled at the substrate active site of aldose reductase. / Rastelli, Giulio; Vianello, Paola; Barlocco, Daniela; Costantino, Luca; Del Corso, Antonella; Mura, Umberto.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 7, No. 14, 22.07.1997, p. 1897-1902.

Research output: Contribution to journalArticle

Rastelli, Giulio ; Vianello, Paola ; Barlocco, Daniela ; Costantino, Luca ; Del Corso, Antonella ; Mura, Umberto. / Structure-based design of an inhibitor modeled at the substrate active site of aldose reductase. In: Bioorganic and Medicinal Chemistry Letters. 1997 ; Vol. 7, No. 14. pp. 1897-1902.
@article{5b64c21924f6496b8843b2f483899f7d,
title = "Structure-based design of an inhibitor modeled at the substrate active site of aldose reductase",
abstract = "This study presents the first successful example of structure-based drug design on aldose reductase in the extant literature. Starting from the structure of the modeled complex of aldose reductase with a pyridazinone acetic acid inhibitor that we previously disclosed, using the tools of molecular modeling for structure manipulation and molecular mechanics for energy minimization, we were able to design and synthesize a new analog that showed remarkably improved activity. We hope that a proper account of the most important enzyme-inhibitor interactions revealed by this study mill allow, in the future, the design of new lead compounds having structures unrelated to carboxylic acids.",
author = "Giulio Rastelli and Paola Vianello and Daniela Barlocco and Luca Costantino and {Del Corso}, Antonella and Umberto Mura",
year = "1997",
month = "7",
day = "22",
doi = "10.1016/S0960-894X(97)00321-1",
language = "English",
volume = "7",
pages = "1897--1902",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "14",

}

TY - JOUR

T1 - Structure-based design of an inhibitor modeled at the substrate active site of aldose reductase

AU - Rastelli, Giulio

AU - Vianello, Paola

AU - Barlocco, Daniela

AU - Costantino, Luca

AU - Del Corso, Antonella

AU - Mura, Umberto

PY - 1997/7/22

Y1 - 1997/7/22

N2 - This study presents the first successful example of structure-based drug design on aldose reductase in the extant literature. Starting from the structure of the modeled complex of aldose reductase with a pyridazinone acetic acid inhibitor that we previously disclosed, using the tools of molecular modeling for structure manipulation and molecular mechanics for energy minimization, we were able to design and synthesize a new analog that showed remarkably improved activity. We hope that a proper account of the most important enzyme-inhibitor interactions revealed by this study mill allow, in the future, the design of new lead compounds having structures unrelated to carboxylic acids.

AB - This study presents the first successful example of structure-based drug design on aldose reductase in the extant literature. Starting from the structure of the modeled complex of aldose reductase with a pyridazinone acetic acid inhibitor that we previously disclosed, using the tools of molecular modeling for structure manipulation and molecular mechanics for energy minimization, we were able to design and synthesize a new analog that showed remarkably improved activity. We hope that a proper account of the most important enzyme-inhibitor interactions revealed by this study mill allow, in the future, the design of new lead compounds having structures unrelated to carboxylic acids.

UR - http://www.scopus.com/inward/record.url?scp=0030854601&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030854601&partnerID=8YFLogxK

U2 - 10.1016/S0960-894X(97)00321-1

DO - 10.1016/S0960-894X(97)00321-1

M3 - Article

AN - SCOPUS:0030854601

VL - 7

SP - 1897

EP - 1902

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 14

ER -