This first introductory-level textbook on the design of small molecules is written with the first-time user in mind. Aimed at students and scientists alike, it uses computer-based methods to design and analyze such small molecules as drugs, enzyme inhibitors, probes and markers for biomolecules. Both authors have extensive practical experience of modeling and design and share their knowledge of what can and cannot be done with computer-assisted design. Divided into four sections, the book begins with a look at molecular objects and design objectives, including molecular geometry, properties, recognition and dynamics. Two further sections deal with virtual synthesis and screening, while the final section covers navigation in chemical space. The result is a textbook that takes the modeler one step further, to the de novo design of functional molecules. With its study questions at the end of each learning unit, this is equally suitable for teaching and self-learning.

Gisbert Schneider is Professor for Chemoinformatics and Bioinformatics at the University of Frankfurt (Germany). He studied Biochemistry, Medicine and Computer Science at the University of Berlin where he also obtained his PhD. He spent postdoctoral terms at the MIT in Cambridge, in Stockholm and Frankfurt before joining Hoffmann-La Roche in Basel. After five years in pharmaceutical research, he became the first Beilstein Professor for Chemoinformatics at the University of Franfurt. In 2006 he won the title "Professor of the Year" in the annual national contest run by the journal "Unicum". KarlHeinz Baringhaus is the Head of Computational Chemistry at Aventis Pharma in Frankfurt (Germany). He studied Chemistry at the University of Münster where he also obtained his PhD degree. After a postdoctoral term at Stanford University he joined the Hoechst AG, where he was appointed head of Molecular Modeling and Computational Chemistry.

Leseprobe

Molecular Objects and Design Objectives - Molecular geometry and surface - Molecular properties - The concept of drug-likeness - Representing molecules as strings Receptor-Ligand Interaction - Thermodynamics of protein-ligand interaction - QSAR: estimating quantitative structure-activity relationships - The biophore concept - Pharmacophores Creating the Design - Rational drug design - Ligand-based design of compound libraries - Transition state analogs - de novo design Virtual Screening - Similarity searching - Pharmacophore-based virtual screening - Molecular docking and scoring - Structure-based vs. ligand-based design - Case study 1: design of Kv1.5 ion channel modulators - Case study 2: virtual screening of a natural-product derived combinatorial library for novel 5-lipoxygenase inhibitors - Case study 3: scaffold de novo design for cannabinoid-1 (CB-1) receptor ligands Secondary design constraints and machine learning - Introduction to Pharmacokinetics - Prodrugs and bioisosters - Machine learning methods - Case study 1: predicting cross-activities of allosteric modulators of metabotropic glutamate receptors (mGluR) - Case study 2: dopamine D3 antagonists and ACE inhbitors