Pharmacophores and Pharmacophore Searches provides a complete overview of the field and progresses from general considerations to real life scenarios in drug discovery research.
Starting with an introductory historical overview, the authors move on to discuss ligand-based approaches, including 3D pharmacophores and 4D QSAR, as well as the concept and application of pseudoreceptors.
The next section on structure-based approaches includes pharmcophores from ligand-protein complexes, FLIP and 3D protein-ligand binding interactions. The whole is rounded off with a complete section devoted to applications and examples, including modeling of ADME properties.
With its critical evaluation of pharmacophore-based strategies, Pharmacophores and Pharmacophore Searches represents a valuable aid for project leaders and decision-makers in the pharmaceutical industry, as well as pharmacologists, and medicinal and chemists
Contents
Introduction
Pharmacophores: Historical Perspective and Viewpoint from a Medicinal Chemist
- Historical Perspective
- Pharmacophores: the Viewpoint of a Medicinal Chemist
Pharmacophore Approaches
Pharmacophore Model Generation Software Tools
- Molecular Alignments
- Pharmacophore Modeling
- Automated Pharmacophore Generation Methods
Alignment-free Pharmacophore Patterns—A Correlation-vector Approach
- The Correlation-vector Approach
- Applications
- New Methods Influenced by the Correlation-vector Approach
Feature Trees: Theory and Applications from Large-scale Virtual Screening to Data Analysis
- Introduction: from Linear to Non-linear Molecular Descriptors
- Creating Feature Trees from Molecules
- Algorithms for Pairwise Comparison of Feature Trees
- Feature Trees in Similarity Searching and Virtual Screening
- Searching Combinatorial Fragment Spaces with Feature Trees
- Multiple Feature Tree Models: Applications in HTS Data Analysis
- Drawing Similar Compounds in 2D Using Feature TreeMappings
Concept and Applications of Pseudoreceptors
- Methodology
- Application of Pseudoreceptors
Pharmacophores from Macromolecular Complexes with LigandScout
- The Data Source: Clean-up and Interpretation of PDB Ligand Molecules
- Chemical Feature-based Pharmacophores Used by LigandScout
- Overlaying Chemical Features
- 3D Visualization and Interaction
- Application Examples: Pharmacophore Generation and Screening
GRID-based Pharmacophore Models: Concept and Application Examples
- Theoretical Basis of the GBPM Method
“Hot Spot” Analysis of Protein-binding Sites as a Prerequisite for Structure-based Virtual Screening and Lead Optimization
- Calculating “Hot Spots”
- From “Hot Spots” to Molecules
- Real-life Examples
- Replacement of Active-site Water Molecules
Application of Pharmacophore Fingerprints to Structure-based Design and Data Mining
- Applications of 3D Pharmacophore Fingerprints
SIFt: Analysis, Organization and Database Mining for Protein-Inhibitor Complexes
- Application to Protein Kinase Inhibitors
- How to Generate a SIFT Fingerprint
- Profile-based SIFTs
- SIFt and the Analysis of Protein Kinase – Inhibitor Complexes
- Canonical Protein – Small Molecule Interactions in the Kinase Family
- Clustering of Kinase Inhibitors Based on Interaction Fingerprints
- Profile Analysis of ATP and CDK2 Complexes
- Virtual Screening
- Use of p-SIFT to Enrich Selectively CDK2 and ATP Complexes
Application of Structure-based Alignment Methods for 3D QSAR Analyses
- Why is 3D QSAR So Attractive?
- CoMFA and Related Methods
- CoMFA
- CoMSIA
- GRID/GOLPE
- Reliability of 3D QSAR Models
- Structure-based Alignments Within 3D QSAR
Pharmacophores for Hit Identification and Lead Profiling: Applications and Validation
Application of Pharmacophore Models in Medicinal Chemistry
- Building Pharmacophore Models Able to Account for the Molecular Features Required to Target the Adrenergic Receptor and its Subtypes
- Use of Excluded Volume Features in the Rationalization of the Activity Data of Azole Antifungal Agents
GPCR Anti-target Modeling: Pharmacophore Models to Avoid GPCR-mediated Side-effects
- GPCRs as Anti-targets
- In Silico Tools for GPCR Anti-target Modeling
- GPCR Anti-target Pharmacophore Modeling: the Adrenergic Receptor
Pharmacophores for Human ADME/Tox-related Proteins
- Cytochrome P450
- UDP-glucuronosyltransferase
- P-glycoprotein (P-gp)
- Human Peptide Transporter 1
- Apical Sodium-dependent Bile Acid Transporter (ASBT)
- Sodium Taurocholate-transporting Polypeptide (NTCP)
- Nucleoside Transporters
- Organic Cation Transporter 1 and 2
- Organic Anion-transporting Polypeptides (OATPs)
- Breast Cancer Resistance Protein (BRCP)
- The Nuclear Hormone Receptors
- Human Ether-a-go-go Related Gene
Are You Sure You Have a Good Model?
- Validation Methods: Different Answers Brought to Different Questions
- A Successful Application: The Ultimate Validation Proof
Index
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