On the validity of popular assumptions in computational drug design
2011
Validity of Assumptions in Computational Drug Design
publication
Author Information
Author(s): Gerhard Klebe, Frank Oellien, Uli Fechner, Thomas Engel
Primary Institution: Inst. of Pharmaceutical Chemistry, University of Marburg
Hypothesis
Do popular assumptions in computational drug design hold true when validated against experimental evidence?
Conclusion
Many popular assumptions in computational drug design, such as perfect shape complementarity and additivity of functional group contributions, may not be valid.
Supporting Evidence
- Computational methods in drug design are often based on oversimplified assumptions.
- High affinity binding can occur even with ligands that do not fit perfectly in the binding pocket.
- The assumption of additivity in drug design can lead to inaccuracies due to molecular cooperativity.
- Entropic contributions to binding are often arbitrarily assumed to be equivalent across similar ligands.
- Protonation states of ligands are often set to standard values, ignoring significant pKa shifts.
- The role of water in ligand binding is complex and can vary significantly between different ligands.
Takeaway
Scientists think that drugs need to fit perfectly in their targets, but that's not always true. Sometimes, drugs can work well even if they don't fit perfectly.
Digital Object Identifier (DOI)
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