3D Molecular Structures.pptVIP

3D Molecular Structures C371 Fall 2004 Morgan Algorithm (Leach Gillet, p. 8) Bioisosteres (Leach Gillet, p. 31) Milestones In Chemical Information: IV (PW) Structure diagrams are planar but molecules are not, so need to extend existing 2D screening and graph-search methods to allow 3D substructure searching (Pfizer and Lederle, 1986-87) Sources of 3D structural data Experimental data (Cambridge Structure Database) Computational chemistry (quantum mechanics, molecular mechanics, molecular dynamics) Structure-generation methods for databases of molecules CONCORD (Texas, 1987) CORINA (Munich/Erlangen, 1990) Further extensions to allow flexible searching (ICI, MDL and Tripos, 1991-94) Milestones In Molecular Modelling: IV (PW) Use of 3D information in QSAR to facilitate structure-based approaches to drug discovery COmparative Molecular Field Analysis (Tripos 1988), and related approaches Calculate energies at points on a 3D grid surrounding a molecule Statistical correlation with activity to identify important positions in space Need for alignment Pharmacophore (Leach Gillet, p. 32) 3D Substructure Searching (PW) Current Activities: Virtual Screening (PW) Need to prioritise the many molecules that could be tested Increasingly sophisticated level of filtering to maximise the numbers of potential leads “Drugability” considerations Similarity searching (both 2D and 3D) using initial weak leads 3D substructure searching once possible pharmacophoric patterns have been identified Docking once the 3D structure of the biological target is available Cambridge Structural Database X-ray crystal structures of more than 250,000 compounds (organic and organometallic) Established in 1965 Textual queries Structural queries Specific 3D constraints (conformation or distance variables) Protein Data Bank More than 25,000 X-ray and NMR structures of protein and protein-ligand complexes Some nucleic acid and carbohydrate structures Founded in 1971 at Brookhaven National Laboratory