Combinatorial Library Design and Evaluation

Ghose, Arup; Viswanadhan, Vellerkad

• Introduction - library design concepts and implementation strategies. Part 1 Design principles: fundamentals of pharmacophore modelling for combinatorial chemistry; quantitative structure-activity relationships (QSAR) - versatile tool in drug design; quantitative structure-activity relationships (QSAR) - a review of 3D QSAR; binding energy landscapes of ligand-protein complexes and molecular docking - principles, methods and validation experiments; fast continuum electrostatics methods for structure-based ligand design; quo vadis, scoring functions? toward an integrated pharmacokinetic and binding affinity prediction framework. Part 2 Current methods and software tools: knowledge-based approaches for the design of small molecule libraries for drug discovery; drug-likeness profiles of chemical libraries; tools for designing diverse, drug-like, cost-effective combinatorial libraries; relative and asbolute diversity analysis of combinatorial libraries; rational combinatorial library design and database mining using inverse QSAR approach; dissimilarity-based compound selection for library design; pharmacore-based approaches to combinatorial library design; high throughput conformational sampling and fuzzy similarity metrics - a novel approach to similarity searching and focused combinatorial library design and its role in the drug discovery laboratory. Part 3 Applications: applications of cell-based diversity methods to combinatorial library design; structure based combinatorial library design and screening - applications of the multiple copy simultaneous search method; genetic algorithm-directed lead generation; enhancement of the drug discovery process by integration of structure-based drug design and combinatorial synthesis; design of structrural combinatorial libraries that mimic biological motifs.