Targets looking for drugs: a multistep computational protocol for the development of structure-based pharmacophores and their applications for hit discovery

Cristina Tintori; Valentina Corradi; Matteo Magnani; Fabrizio Manetti; Maurizio Botta

doi:10.1021/ci800105p

Targets looking for drugs: a multistep computational protocol for the development of structure-based pharmacophores and their applications for hit discovery

J Chem Inf Model. 2008 Nov;48(11):2166-79. doi: 10.1021/ci800105p.

Authors

Cristina Tintori¹, Valentina Corradi, Matteo Magnani, Fabrizio Manetti, Maurizio Botta

Affiliation

¹ Dipartimento Farmaco Chimico Tecnologico, Universita di Siena, Via Aldo Moro, I-53100 Siena, Italy.

PMID: 18942779
DOI: 10.1021/ci800105p

Abstract

Pharmacophoresthree-dimensional (3D) arrangements of essential features enabling a molecule to exert a particular biological effectconstitute a very useful tool in drug design both in hit discovery and hit-to-lead optimization process. Two basic approaches for pharmacophoric model generation can be used by chemists, depending on the availability or not of the target 3D structure. In view of the rapidly growing number of protein structures that are now available, receptor-based pharmacophore generation methods are becoming more and more used. Since most of them require the knowledge of the 3D structure of the ligand-target complex, they cannot be applied when no compounds targeting the binding site of interest are known. Here, a GRID-based procedure for the generation of receptor-based pharmacophores starting from the knowledge of the sole protein structure is described and successfully applied to address three different tasks in the field of medicinal chemistry.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology
Binding Sites
Databases, Factual
Dimerization
Drug Discovery / statistics & numerical data*
Drug Evaluation, Preclinical / statistics & numerical data
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
HIV Integrase Inhibitors / chemistry
HIV Integrase Inhibitors / pharmacology
HIV Reverse Transcriptase / antagonists & inhibitors
HIV Reverse Transcriptase / chemistry
Humans
Informatics
Models, Molecular
Molecular Structure
Pharmaceutical Preparations / chemistry*
Protein Conformation
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology
Thioredoxin-Disulfide Reductase / antagonists & inhibitors
Thioredoxin-Disulfide Reductase / chemistry
User-Computer Interface

Substances

Anti-HIV Agents
Enzyme Inhibitors
HIV Integrase Inhibitors
Pharmaceutical Preparations
Reverse Transcriptase Inhibitors
Thioredoxin-Disulfide Reductase
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase