ROCS Ligand Shape Similarity

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ROCS Ligand Shape Similarity

• George Vacek
• August 25, 2004

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Agenda

• Shape Theory
• Basic ROCS usage
• Using VIDA to visualize results
• Using the Color Force Field
• Examples

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Shape Similarity Rigorous Definition

• The difference in the characteristic function, c,
  across all space
• That is, the distance apart in Shape space
• Solving Dmin yields maximal overlap
• D, Dmin are metric properties

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Characteristic Function Gaussian Atoms

• Atoms are Gaussians, not hard spheres
• Gaussians capture the volume correctly
• Full Gaussian expansion not necessary
• Easily integrable, analytic derivatives
• Easily calculate overlap of two atoms
• Product of 2 Gaussians is another Gaussian

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Shape Tanimoto

• Tanimoto
• Shape Tanimoto uses 3D overlap instead of bits
  comparison
• Interesting values in different range than 2D
• Sensitive to large size differences between two
  structures

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Shape Tversky

• Tversky
• 2D version by John Bradshaw at Daylight
• Useful for small structure vs. large structure
• Weighting factor for size differences
• Typically asymmetric with ? 0.95, ? 0.05
• Field measure not strictly limited 0,1

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Similar Shapes
Shape Tanimoto gt 0.7
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Simple Example

• ROCS requires only 2 inputs
• a file containing shape query molecules
• a file containing the database of interesting
  structures
• corporate database, ACD-Screen, vendor databases
  etc.
• Must already be 3D
• File format can be SDF, MOL2, PDB, XYZ, MMOD, OEB
  
• rocs -dbase vendor.oeb.gz -query 6cox.mol2

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Other Default Settings

• -besthits 500
• number of results to keep in hitlist
• -cutoff 0.0
• minimum score to even consider
• -rankby tanimoto
• alternates tverskyd, tverskyq, scaledcolor,
  combo
• -prefix rocs
• text prefix for output file names
• -oformat sdf
• format of output structure file

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Initial Orientation

• Default - Inertial Frame alignment
• Overlay center of mass
• Align largest moment of inertia, then second
  largest
• each 2-fold degeneracy yields 4 starting points
• Extra 2 or 4 axes for top symmetry
• Random
• -randomstarts N

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More Simple Examples

• rocs -dbase spam.bin -query acetsali.sdf
• -prefix ACET -cutoff 0.5 -besthits 100
• -outputquery
• rocs -dbase spam.bin -query aminopy.sdf
• -rankby tverskyd -cutoff 0.4 -besthits 10
• -outputquery

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Analyze Results

• ROCS outputs a structure file and a report file
• Structure file is SDF (by default)
• scores are stored in SD tags
• automatically loaded into VIDAs spreadsheet
• Report file is tab-delimited text
• load into any spreadsheet for analysis, or
• parse by splitting each line on tabs

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Color Force Field

• Color atoms or groups of atoms with SMARTS to
  describe pharmacophores
• Report color score only
• Optimize overlay along color gradients

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Color Definitions

• Define some atom types

TYPE donor TYPE acceptor TYPE cation TYPE
anion TYPE rings
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Color Definitions

• Define SMARTS pattern for each type

These definitions of donor and acceptor are the
general definitions of Mills Dean, JCAMD
10607-622, 1996. Donor an electronegative
atom with a proton (no S or C, see
above). PATTERN donor
7,8h,H Acceptor a lone pair on an
electronegative atom (O or N S was removed,
see reference). Note, N in an amide or in an
alkyl-aniline system is too conjugated to
accept, however, analinic NH2 is a potential
acceptor. PATTERN acceptor
OD1(O-,,6,15,16)!(1,2,3) PATTERN
acceptor nH0,N,8!(nX3)((-,
,ee)-,,ee)! (NC)!(ND2,D3-a)!(
1,2,3) PATTERN acceptor
NX3((-,,ee)(-,,ee)-,,ee)!(
1,2,3)
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Included Force-fields

• simple.cff very simple color force field
• MillsDean.cff more complete
• Mills-Dean definitions of donors and acceptors
• Mills Dean, J. Comp.-Aid. Mol. Design, 10
  (1996) 607-622
• rings, anions and cations

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Color Force-field

• Define interactions between atom types
• Weight is strength of interaction, relative to
  shape gradients.
• Radius affects range of interaction

INTERACTION donor donor attractive gaussian
weight1.0 radius1.0 INTERACTION acceptor
acceptor attractive gaussian weight1.0
radius1.0 INTERACTION rings rings attractive
gaussian weight1.0 radius1.0
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Roadmap for ROCS 2.1

• General grid query
• New-and-improved hitlist
• Memory management for large runs
• Improved management for parallel jobs
• Other optimizations