Shape

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Shape

• A sculptor is a person obsessed with the form
  and shape of things, and its not just the shape
  of one thing, but the shape of anything and
  everything
• -Henry Moore

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Fundamental QuestionWhen are Two Things the
Same Shape?
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Shape Similarity Implies Volume Overlap
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Shape Is Not Size Invariant
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Volume Difference Measures Shape Dissimilarity
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Desperately Seeking Dmin

• Masek - Skinny
• Hard Sphere
• Slow (100s), Non-Robust
• Grant, Pickup
• Hard Spheres -gt Gaussians (1/s)
• Nicholls, Stahl
• ROCS ( 800/s)

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Properties of Dmin

• Global, steric similarity
• Global minimization problem
• Globally useful-
• Initial search Diverse shapes
• Elucidation Is shape important?
• Similarity Similar function
• Difference Not chemical

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Fundamental Goal of OpenEye

• There may be 10200 synthetically available
  molecules but how many are needed to cover Shape
  Space and Electrostatic Space?

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ROCS(Rapid Overlap of Chemical Structures)

• Represents atoms as Gaussians of equivalent
  volume
• Uses Moments of Inertia as initial orientations
• Fast, quasi-Newton optimization in quaternion
  space (10-3s)
• SMARTS defined color forces which can be used
  during optimization or to score the overlay
• PVM-enabled

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Shape Tanimoto
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ROCStories

• Jumping Lead Series
• fast followers (AZ)
• dead ends (AZ, Scios)
• unusable screening hits (Wyeth)
• HTS rescue (Scios, Wyeth, AZ)
• Partial Shape Match (AZ, Wyeth)
• Protein Alignment (Boehringer-I.)

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Additional

• AZ routinely screen 109 conformers in 23 hours
• Chemistry is best as a post-alignment score
• Shape alone is often enough
• When its not, simple modifications suffice
• It really engages chemists

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SHAPE

• SHAPE is a toolkit implementation of ROCS, e.g.
  best overlay, chemistry etc.
• Very low-level, Daylight-like, API
• Random-starts, multiple alignments, external
  functions, static overlays, steric multipoles,
  access to optimizer.
• Generalization of objects molecules and grids,
  (ellipsoids, surfaces and more).