FRED: Fast Rigid Exhaustive Docking
FRED: Fast Rigid Exhaustive Docking
FRED: Fast Rigid Exhaustive Docking
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<strong>FRED</strong>: <strong>Fast</strong> <strong>Rigid</strong> <strong>Exhaustive</strong><br />
<strong>Docking</strong><br />
CUP VII<br />
Paul Hawkins
Outline<br />
• DOES<br />
– Target “intermediate” users<br />
– Begin with basics<br />
– Examine some of <strong>FRED</strong>’s options<br />
• DOES NOT:<br />
– Target advanced/experienced users<br />
– Give “tips and tricks”
The Scheme of Things….<br />
FILTER remove undesirables<br />
OMEGA conformations<br />
<strong>FRED</strong> docking<br />
Szybki MMFF refinement
How does <strong>FRED</strong>2.1 work?<br />
• Input conformer database<br />
– Optimised with OMEGA, others permissible.<br />
• Place rigid conformers within binding site<br />
box<br />
• Filter based on inclusion within negative<br />
image<br />
• Score and rank
The box
<strong>FRED</strong> negative image
Pose Ensemble Generation<br />
Rotations Translations<br />
Negative image<br />
Size of the ensemble depends on<br />
• Size of the active site<br />
• Size of the ligand<br />
• Number of conformers<br />
• Rotational and Translational stepsize
Generation of Candidate Poses :<br />
<strong>Exhaustive</strong> <strong>Docking</strong><br />
Ligand Conformers<br />
Pose Ensemble Generation<br />
Clash and Distance Filter<br />
Constraint Filter<br />
Score Poses<br />
with Chemgauss2<br />
Filter Low<br />
Scoring Poses<br />
Optimize vs<br />
Chemgauss2<br />
100 Candidate Poses
Consensus Pose Prediction<br />
100 best poses<br />
Solid body optimisation - PLP<br />
Scoring with all s.f’s<br />
Consensus selection Sum by rank<br />
MMFF<br />
refinement<br />
Scoring<br />
1 Predicted Pose
<strong>FRED</strong>2: Preparation<br />
• Database to dock<br />
– dbase NAME<br />
– conftest TEST_METHOD<br />
– molnames FILE (list)<br />
• Protein<br />
– pro FILE (PDB)<br />
– box FILE (XYZ or ligand)<br />
– addbox DISTANCE<br />
– pharm FILE
<strong>FRED</strong>2: <strong>Exhaustive</strong> search<br />
• Placement<br />
– tstep and rstep DISTANCE<br />
• Poses<br />
– num_poses NUMBER<br />
– num_alt_poses NUMBER<br />
• Scoring<br />
– clash_checking & neg_img_size NUMBER<br />
– exhaustive_scoring METHOD
<strong>FRED</strong>2: Scoring<br />
• Optimisation<br />
– optimization NAME<br />
• Scoring functions<br />
– Names BOOLEAN<br />
• Scoring function parameters<br />
– Names NUMBER<br />
• Scoring pre-placed poses<br />
– no_dock BOOLEAN
<strong>FRED</strong>2: Alternate poses<br />
• Extra poses<br />
– num_alt_poses INTEGER<br />
– sort_by_top_consensus_pose BOOLEAN<br />
• MMFF refinement<br />
– lig_refine STRING
• Title and format<br />
– prefix NAME<br />
– oformat NAME<br />
<strong>FRED</strong>2: Output<br />
– output_structures BOOLEAN<br />
– serial BOOLEAN
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