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Sulfonamide-related conformational effects and their importance in structure-based design
Stefan Senger1, Chuen Chan, Máire A Convery
1GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. stefan.x.senger@gsk.com
Bioorganic & Medicinal Chemistry Letters
|March 6, 2007
Summary
Structure-based design (SBD) is complex, but this study shows conformational effects can dominate biological activity differences. These findings offer a qualitative guide for future SBD efforts.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Structural Biology
Background:
- Structure-based design (SBD) often faces challenges in explaining localized structure-activity relationships (SAR).
- Identifying single dominant factors for SAR is typically difficult in drug discovery.
Purpose of the Study:
- To present a rare case where conformational effects are the primary driver of biological activity differences.
- To demonstrate the utility of integrating structural information with ab initio calculations in SBD.
- To establish a qualitative guide for SBD based on conformational analysis.
Main Methods:
- Utilized structural information and ab initio calculations.
- Analyzed conformational effects influencing biological activity.
- Validated the findings through experimental testing.
Main Results:
- Identified conformational effects as the dominant factor in observed biological activity differences.
- Demonstrated a successful application of integrated computational and structural approaches.
- Confirmed the practical utility of the derived SBD guidance.
Conclusions:
- Conformational effects can be a key determinant in SBD, even when seemingly localized SAR is observed.
- The combination of structural data and ab initio methods provides valuable insights for drug design.
- The developed qualitative guide can enhance the efficiency and success rate of SBD initiatives.
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