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3D molecular descriptors important for clinical success
David C Kombo1, Kartik Tallapragada, Rachit Jain
1Targacept, Inc., 200 East First Street, Suite 300, Winston-Salem, North Carolina 27101-4165, USA. dckombo777@mail.com
Journal of Chemical Information and Modeling
|December 19, 2012
Summary
Shape-based 3D molecular descriptors, like shadow indices, better predict drug success than 2D descriptors. Spherical compounds with few aromatic rings are more likely to reach the market.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Computational Chemistry
Background:
- Physicochemical properties significantly impact drug candidate pharmacokinetics and safety.
- 2D molecular descriptors like fraction of Sp3 carbon atoms (Fsp3) and stereo centers have shown correlation with clinical success.
- However, their ability to predict off-target promiscuity and clinical success is limited.
Purpose of the Study:
- To evaluate the predictive power of 3D shape-based molecular descriptors for drug clinical success.
- To identify key molecular descriptors that discriminate between successful and withdrawn drug candidates.
- To establish criteria for non-promiscuous ligands and compounds likely to advance through clinical trials.
Main Methods:
- Analysis of proteomic off-target hit rates for nicotinic ligands.
- Utilized shape-based 3D descriptors (radius of gyration, shadow indices) and 2D descriptors (Fsp3, stereo centers, LogD).
- Investigated the MDL Drug Data Report (MDDR) database for compounds from preclinical to market stages.
Main Results:
- 3D shape descriptors better predicted off-target promiscuity compared to Fsp3 and stereo centers.
- 3D descriptors accurately predicted clinical success in preclinical and Phase 1 stages versus withdrawn compounds.
- Launched drugs (84%) met Shadow index or Fsp3 criteria, unlike withdrawn compounds.
- Computed 3D descriptors correlated with experimental solubility, a key factor in clinical success.
Conclusions:
- Shape-based 3D molecular descriptors are superior predictors of clinical success and reduced off-target effects.
- Spherical compounds with minimal aromatic rings show higher potential for successful clinical progression.
- These findings offer valuable insights for designing drug candidates with improved clinical outcomes.
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