Design of Small Molecule Drugs Targeted to RNA

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Design of Small Molecule Drugs Targeted to RNA

• RNA Ontology Group
• May 29 2007

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Small Molecule and Large Molecule Drug Design

• Small Molecule Drugs
• Low MW
• Moderately hydrophobic/hydrophilic
• Moderately chemical complexity
• Biologicals
• Peptides/peptidomimetics
• Engineered enzymes
• Antisense/RNAi
• Need help to enter cells!

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New Tools for Drug Discovery (1980s and 90s)

• Combinatorial Chemistry
• Increased the number of available compounds
• High Throughput Screening (HTS)
• Increases throughput for testing (robotics,
  databasing)
• Its a Numbers Game

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Rational Drug Design the Opposite of Its a
Numbers Game
Protein Structure
Design small molecule to fit and block active
site
Voila!
Doesnt work!
In Silico High Throughput Docking A rational
numbers game
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Membrane Permeability Drug-Likeness

• The Lipinski Rule of Five

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Fragment Library Design

• Fragments must be lead-like not drug-like
• MW lt 250, allows compound to grow
• Weak binding affinity (will add affinity with
  growth)
• Contain polar groups
• Insures solubility
• Polar groups are reactive
• Pick up hydrogen bonding interactions
• N fragments can cover the chemical space of N2
  compounds

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Lipinski Rule of 5

• Molecular Weight lt 500 Daltons
• cLogP lt 5
• lt 10 Acceptor Groups (ON)
• lt 5 Donor Groups ( O-H, N-H)
• Exceptions work by active transport

Thiostrepton MW 1665
Paromomycin MW 616
Erythromycin MW 734
Tetracycline MW 444
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Examples of Small Molecule Molders/Regulators of
RNA Secondary Structure in Bacteria
SAH No effect
SAM Kd20-200 nM
2,6 diaminopurine Kd10 nM
Purine Kd100 µM
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Examples of Small Molecule Molders/Regulators of
RNA Secondary Structure in Bacteria
Riboflavin Kd3 µM
FMN Kd5 nM
L-Lysine Kd1 µM
D-Lysine No effect
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RNA-binding
Protein-binding
b
a
c
druggable
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Current Databases

• Pdb title search RNA gets 2173 hits ternary
• Structure description search for ribonucleic
  acid 6 hits (2 DNA)
• NDB search for RNA ligand 841 hits, including
  protein/RNA complex
• Most ligand databases oriented to search for
  proteins/ligands

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Database of RNA Binding Compounds

• Antibiotics
• Riboswitch ligands
• Drug discovery programs (published)
• Published findings of natural products
• 105 compounds in all

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Database of RNA Binding Compounds (caveats)

• Only 25 compounds had pdb coordinates
• Reported Kd lt 50 µM
• Redundancy does not include near neighbors
• pdb coordinates did not identify non-contacting
  substructures

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Database of RNA Binding Compounds (further needs)

• DNA binding compounds
• Classification
• Correlation with RNA motifs/pharmacophores

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(No Transcript)
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Fragment based approaches

• gt500k compounds screened
• assays usually require mM hits
• Template decoration often prevents interaction
• Need to reduce MW of weak binders prior
• to modification

HTS requires right compounds in library