Molecular Similarity in Drug Design

Molecular similarity searching is fast becoming a key tool in organic chemistry. In this book, the editor has brought together an international team of authors, each working at the forefront of this technology, providing a timely and concise overview of current research. The chapters focus principally on those methods which have reached sufficient maturity to be of immediate practical use in molecular design.

Table of Contents:
1 Defining molecular similarity and complementarity for drug design.- 1.1 Introduction.- 1.2 Problems in using molecular similarity methods for drug design.- 1.3 Extraction of molecular similarity from two or more molecules.- 1.4 Molecular design based on molecular similarity.- 1.5 Conclusions.- 2 3D molecular similarity indices and their application in QSAR studies.- 2.1 Introduction.- 2.2 An index of indices.- 2.3 The ultimate index.- 2.4 Molecular superposition and property evaluation.- 2.5 Molecular similarity data in QSAR.- 2.6 Conclusions.- 3 The treatment of conformationally flexible molecules in similarity and complementarity searching.- 3.1 Introduction.- 3.2 Methods for exploring conformational space: a summary.- 3.3 Systematic search methods.- 3.4 Model-building approaches.- 3.5 Random search methods.- 3.6 Choosing the structure to be randomised.- 3.7 Simulated annealing.- 3.8 Distance geometry.- 3.9 Genetic algorithms.- 3.10 Molecular dynamics.- 3.11 Conformational analysis in similarity searching.- 3.12 Conformational aspects of complementarity searching.- 3.13 Conformational flexibility in 3D database searches.- 3.14 Conclusions.- 4 Exploiting similarity between highly flexible and dissimilar molecular structures.- 4.1 Introduction.- 4.2 Molecular conformation.- 4.3 Similarity and conformation.- 4.4 Exploitation of matches.- 4.5 Conclusions.- 5 Similarity-searching and clustering algorithms for processing databases of two-dimensional and three-dimensional chemical structures.- 5.1 Introduction.- 5.2 Evaluation of effectiveness.- 5.3 Clustering databases of 2D structures.- 5.4 Similarity searching in databases of 3D structures.- 5.5 Similarity searching in databases of 3D protein structures.- 5.6 Conclusions.- 6 Experiences with searching for molecular similarity in conformationally flexible 3D databases.- 6.1 Introduction.- 6.2 Creation of a viable 3D database.- 6.3 Identification of new leads by 3D database pharmacophoric searching.- 6.4 Generation and optimisation of novel leads using 3D databases.- 6.5 Conclusion.- 7 Molecular surface comparisons.- 7.1 Introduction to surface similarity and complementarity.- 7.2 Defining molecular surfaces.- 7.3 Surface comparison: alignment and conformation.- 7.4 Methods.- 7.5 Methods utilizing surfaces with thickness.- 7.6 Conclusion.- 8 Neural networks in the search for similarity and structure-activity.- 8.1 Introduction.- 8.2 What are neural networks?.- 8.3 Applications.- 8.4 Summary.- 9 Molecular similarity and complementarity based on the theory of atoms in molecules.- 9.1 Introduction.- 9.2 The charge density as starting point.- 9.3 Selected topics from AIM.- 9.4 Similarity.- 9.5 Complementarity.- 9.6 Example: haloperidol.- 9.7 Conclusion.- 9.8 Future developments.- 10 Methods of molecular shape similarity and topological shape design.- 10.1 The role of shape analysis in drug design.- 10.2 Electron-density computations for large molecules.- 10.3 The topology of molecular shape: basic concepts.- 10.4 Numerical shape codes and measures of molecular similarity and complementarity.- 10.5 Summary.- 11 The application of molecular topology to drug design—topological descriptions of molecular shape.- 11.1 Introduction.- 11.2 Graphs, surfaces and topology.- 11.3 Shape sequences.- 11.4 Shape graphs.- 11.5 Conclusions and future directions.- 12 Comparative molecular field analysis (CoMFA).- 12.1 Introduction.- 12.2 Biological data.- 12.3 Selection of compounds and series design.- 12.4 Generation of three-dimensional structure of the ligand molecules.- 12.5 Conformational analysis ofeach molecule.- 12.6 Establishment of the bioactive conformation of each molecule.- 12.7 Superimposition of the molecules.- 12.8 Calculation of the interaction energies.- 12.9 Pretreatment of data.- 12.10 Statistical analysis of the data and selection of 3D-QSAR model.- 12.11 Display of the results in contour plots and their interpretation.- 12.12 Design and forecasting the activity of unknown compounds.- 12.13 Miscellaneous aspects of CoMFA.- 12.14 Checklist for CoMFA publications.