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AMMOS: Automated Molecular Mechanics Optimization tool for in silico Screening
Tania Pencheva1, David Lagorce, Ilza Pajeva
1INSERM U648, Bioinformatics-MTI University Paris Diderot, 5 rue Marie-Andrée Lagroua, 75205 Paris Cedex 13, France. tania.pencheva@clbme.bas.bg
BMC Bioinformatics
|October 18, 2008
Summary
The AMMOS program refines small molecule structures and protein-ligand complexes for drug discovery. This computational tool improves virtual screening efficiency by optimizing molecular interactions and accounting for receptor flexibility.
Area of Science:
- Computational Chemistry
- Drug Discovery
- Molecular Modeling
Background:
- Virtual screening accelerates drug discovery by identifying lead compounds.
- Existing methods struggle with compound structural optimization, receptor flexibility, and accurate interaction prediction.
- Post-docking optimization enhances the efficiency of structure-based virtual screening.
Purpose of the Study:
- To develop the AMMOS program for refining 3D structures of small molecules and protein-ligand complexes.
- To incorporate molecular mechanics optimization allowing for partial to full atom flexibility.
- To address limitations in current virtual screening software.
Main Methods:
- AMMOS automates structural refinement of compound libraries and energy minimization of protein-ligand complexes using the AMMP program.
- Evaluated AMMOS performance by comparing minimized structures with Tripos and MMFF94s force fields.
- Applied AMMOS for flexible minimization of complexes from multi-step virtual screening and conducted enrichment studies.
Main Results:
- AMMOS successfully refined small chemical entity structures compared to established force fields.
- AMMOS improved enrichment in virtual screening, with 40-60% of active compounds found in the top 3-5% after minimization.
- The program demonstrated effectiveness on protein targets with varying binding pocket characteristics.
Conclusions:
- The open-source AMMOS program aids in silico drug design, including small molecule optimization and protein-ligand complex minimization.
- AMMOS enhances virtual screening by refining pre-docked ligands and considering receptor binding site flexibility.
- The tool is valuable for post-processing steps in structure-based drug design studies.
