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. 2008 Oct 16;9:438.
doi: 10.1186/1471-2105-9-438.

AMMOS: Automated Molecular Mechanics Optimization Tool for in Silico Screening

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Free PMC article

AMMOS: Automated Molecular Mechanics Optimization Tool for in Silico Screening

Tania Pencheva et al. BMC Bioinformatics. .
Free PMC article

Abstract

Background: Virtual or in silico ligand screening combined with other computational methods is one of the most promising methods to search for new lead compounds, thereby greatly assisting the drug discovery process. Despite considerable progresses made in virtual screening methodologies, available computer programs do not easily address problems such as: structural optimization of compounds in a screening library, receptor flexibility/induced-fit, and accurate prediction of protein-ligand interactions. It has been shown that structural optimization of chemical compounds and that post-docking optimization in multi-step structure-based virtual screening approaches help to further improve the overall efficiency of the methods. To address some of these points, we developed the program AMMOS for refining both, the 3D structures of the small molecules present in chemical libraries and the predicted receptor-ligand complexes through allowing partial to full atom flexibility through molecular mechanics optimization.

Results: The program AMMOS carries out an automatic procedure that allows for the structural refinement of compound collections and energy minimization of protein-ligand complexes using the open source program AMMP. The performance of our package was evaluated by comparing the structures of small chemical entities minimized by AMMOS with those minimized with the Tripos and MMFF94s force fields. Next, AMMOS was used for full flexible minimization of protein-ligands complexes obtained from a mutli-step virtual screening. Enrichment studies of the selected pre-docked complexes containing 60% of the initially added inhibitors were carried out with or without final AMMOS minimization on two protein targets having different binding pocket properties. AMMOS was able to improve the enrichment after the pre-docking stage with 40 to 60% of the initially added active compounds found in the top 3% to 5% of the entire compound collection.

Conclusion: The open source AMMOS program can be helpful in a broad range of in silico drug design studies such as optimization of small molecules or energy minimization of pre-docked protein-ligand complexes. Our enrichment study suggests that AMMOS, designed to minimize a large number of ligands pre-docked in a protein target, can successfully be applied in a final post-processing step and that it can take into account some receptor flexibility within the binding site area.

Figures

Figure 1
Figure 1
Schematic diagram of the AMMOS procedure. The arrows show the cycle of the automated procedure for a large number of ligands.
Figure 2
Figure 2
Structural refinement of four small molecules with AMMOS (magenta), MMFF94s (cyan) and Tff (yellow). The minimized structures are superimposed on the corresponding X-ray structures (all atom colored). Raloxifene (A), FDI (B), thymidine (C) and PR2 (D).
Figure 3
Figure 3
Energy minimization results for a chemical library of 37970 small organic molecules. A. Scatter-plot of the energy differences ΔE in kcal/mol between the AMMOS minimized and initial structures; B. Pieplot of the ΔE distribution.
Figure 4
Figure 4
RMSD (Å) between the AMMOS minimized and X-ray structures for the inhibitors retrieved for the ER and NA targets. A. Each point represents a single conformer minimized with case 1 (black), case 2 (grey); Triangles refer to the conformers with lowest energy after AMMOS minimization; B. All conformers are represented by points, with respectively black for case 3, grey for case 4 and white for case 5. Triangles refer to the conformers with lowest energy after AMMOS minimization.
Figure 5
Figure 5
Enrichment graphs for ER (A) and NA (B) inhibitors after AMMOS minimization and rescoring. The y-axis is the % of retrieved actives versus the percentage of the database screened (x-axis): enrichment results after flexible docking step (blue); enrichment results after re-scoring employing AMMOS minimization: case 3 (red), all protein atoms inside a sphere around the ligand can move; case 4 (magenta), all side chain protein atoms inside a sphere around the ligand can move; case 5 (green), the whole protein is rigid.

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