Shape and Electrostatics in Lead Discovery

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Shape and Electrostatics in Lead Discovery

• Matthew Stahl, Robert Tolbert, Anthony Nicholls
• OpenEye Scientific Software

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Common Search Tools

• Electrostatic complementarity
• 2D Similarity
• Pharmacophores
• Shape complementarity
• 2D Similarity
• Pharmacophore
• Surface
• Volume

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Definition of Shape
Two entities (molecules) have the same shape if
their volumes exactly correspond.
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What is ROCS?

• Database search tool
• Shape
• Pharmacophores
• Uses
• Scaffold jumping
• HTS rescue
• Patent busting

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Virtual Screening Pipeline
Compounds
Omega
Multi-conformer database
ROCS
Shape hits
ROCS
Chemistry hits
Humint
Screening
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Rocs Algorithm

• Align query molecule
• Convert query to gaussian representation
• Align database molecule
• Convert database molecule to gaussian
  representation
• Solid-body optimization of gaussian overlaps from
  4-fold degenerate positions
• Calculate similarity measure based on overlap
  volumes

Grant Pickup, J. Phys. Chem, 993503-3510 1995
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Similarity Measures
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Color Score
INTERACTION donor donor attractive gaussian
weight1.0 radius1.0
Mills Dean, JCAMD 10607-622, 1996
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It Works!

• How many 'hits' has ROCS helped to identify?
• 15-20, 4 classes, 15-20, 1, 1, 1, 50-75
• How many Targets attempted?
• 5, 4, 3, 1, numerous
• What are typical hit rates?
• 1-2, 6-15, 5-10, 2-5
• How many hits have made it into chemistry
• 0, 1-2, 3, 1, 1, 1
• How many HTS programs have been cancelled?
• gt1?

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E-mail
Got another ROCS success story. Screened a
million molecules, selected 12 that were
commercially available. Found two were already
in our in-house collection. One of them was a
hit missed by the first round of HTS - single
digit uM. Made my afternoon.
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Observations

• ROCS is not a replacement for HTS
• Shape matching is an excellent method for idea
  generation
• ROCS has proven to be an effective technology