Chem167_L12_May14

whereasre likely to be less usefulpositions tfhey

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Unformatted text preview: search t o t he docking o molecules b simbased gridenergetically favorablefpositions forythese smaller fragments h as been to calculate, ~ e n t l y ulated annealing a re simpler described r esuch po- . ~ Whereasre likely to be less usefulpositions tfhey hese sitions a energetically favorable because or t may smaller fragments a re simpleratoarger ligand. Morebe sterically unattainable for l calculate, such positionsn t he ikely toofe igands i t is because they have over, i a re l design b l less useful important t o may orientational, a s well a f p a larger information be sterically unattainable s or ositional,ligand. More- Computa9onal solvent mapping Computa9onal solvent mapping •  14 organic probes to flood receptor surface •  Probes clustered and ranked by interac/on energy with surface •  Hot spots indicate areas of high func/onal group affinity Brenke R, Kozakov D, Chuang G- Y, Beglov D, MaYos C, and Vajda S, Bioinforma/cs. hYp://]map.bu.edu/ De novo approaches (LUDI) Predic9ng PK proper9es QikProp (Schrodinger): -   octanol/water par//on coefficient and water/gas logP’s -   Overall CNS ac/vity (BBB permeability) -   Caco- 2 and MDCK cell permeabili/es -   Assessments of serum albumin binding -   Predic/on of metabolites -   Assessment of “drug- likeness”, Lipinski’s “rule- of- five” ~40% of drug candidates fail in clinical trials because of poor ADME proper:es Grand challenge areas Protein folding & Protein- protein docking D. Baker Lab, U Washington Combinatorial Chemistry Chapter 16 May 13, 2013 What are some different ways to generate lead compounds? Lead genera/on Disadvantages of tradi9onal med chem? Complex and /me consuming Insufficient diversity for new lead discovery Synthe/c output too small Slow development of SAR profiles within a class of compounds •  Slow op/miza/on in evolu/onary cycles •  Insufficient patent coverage •  High costs •  •  •  •  Combinatorial chem •  Uses molecular scaffolds to construct libraries of similar compounds •  Allows high throughput screening (HTS) to search through many similar lead compounds •  Exploits instrumenta/on & robo/cs + computers to efficiently control rxn processes and analyze resul/ng data •  Success tends to depend on the complexity of the...
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This note was uploaded on 01/15/2014 for the course CHEM 167 taught by Professor Amaro during the Winter '13 term at UCSD.

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