By Sun Hongmao
This e-book won't be an exhaustive survey masking all facets of rational drug layout. as a substitute, it's going to supply serious knowledge via real-world examples. suitable case stories can be awarded and analyzed to demonstrate the next: find out how to optimize a lead compound even if one has excessive or low degrees of structural info; how you can derive hits from rivals' energetic compounds or from typical ligands of the objectives; tips on how to springboard from rivals' SAR wisdom in lead optimization; tips to layout a ligand to intervene with protein-protein interactions through accurately studying the PPI interface; find out how to sidestep IP blockage utilizing facts mining; the way to build and completely make the most of a knowledge-based molecular descriptor procedure; the way to construct a competent QSAR version by means of targeting facts caliber and correct collection of molecular descriptors and statistical ways. a pragmatic consultant to Rational Drug layout makes a speciality of computational drug layout, with basically simple assurance of biology and chemistry concerns, comparable to assay layout, goal validation and artificial routes. Read more...
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Additional info for A practical guide to rational drug design
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27. 28), lipophilic substituents, such as ethyl, isopropyl, cyclopropyl, and t-butyl, are preferred, but at R2 or R3 position, a hydroxyl group is beneficial. 29). 28 The design ideas aiming at better electrostatic complementarity for ethamivan improve the potency by 14,000 fold, as determined by isothermal titration calorimetry. 29 Alignment of ethamivan (Protein Data Bank [PDB] ID: 2XDL), colored in magenta, and Radicicol (PDB ID: 4EGK), colored in light gray, at the adenosine-5'triphosphate (ATP) binding site of human heat shock protein 90 (Hsp90).
For example, adding a benzyl group (HA = 7) requires a 30-fold increase in binding affinity to maintain the same LE. In lead optimization, sacrificing LE is typically a step in the wrong direction. Taking the DYRK1A case discussed in Chapter 1 (Fig. 6) as an example, it might not be considered a good design to add 10 heavy atoms to trade for only an 8-fold of increment in the binding affinity. In conclusion, 6-(3-thiophen)-2-aminoquinoline is a high LE BACE1 inhibitor and an appropriate lead compound for the human BACE1 target.
A practical guide to rational drug design by Sun Hongmao