An iterative algorithm for metabolic networkbased drug target identification

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An iterative algorithm for metabolic
network-based drug target identification

• Padmavati Sridhar, Tamer Kahveci, Sanjay Ranka
• Department of Computer and Information Science
  and Engineering
• www.cise.ufl.edu/tamer

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Drug Discovery Process
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Why Drugs?

• Excessive production or lack (or a combination of
  the two) of certain compounds may lead to
  disease.
• Example Malfunction (Phenylalanine hydroxylase)
  gt accumulation of phenylalanine gt
  Phenylketonuria gt mental retardation.
• Drugs can manipulate enzymes to reduce or
  increase the production of compounds !

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An Example Targets for Affecting Central Nervous
System
Drug Phenylbutazone (Therapeutic category 1144)
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Goal

• Given a set of target compounds, find the set of
  enzymes whose inhibition stops the production of
  the target compounds with minimum side-effects.

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Directed Graph Model
Edges
Vertices
Catalyzes
Enzyme
Reaction
Produces
Compound
Consumes
Target compound
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Simple Metabolic Network
E2
R3
C5
E3
R4
R1
C2
C3
R2
E1
C4
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Inhibit E1
E2
R3
C5
E3
R4
R1
C2
C3
R2
E1
C4
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Inhibit E2 or/and E3
E2
R3
C5
E3
R4
R1
C2
C3
R2
E1
C4
Damage (E1) 3
Damage (E2) 0 Damage (E3) 0

• What is the best enzyme combination?
• Number of combinations is exponential !

Damage (E2, E3) 1
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How can we find the right enzyme set?

• Iterative method
• Initialization Remove each node (reaction or
  compound or enzyme) from graph directly.
• Iteration Improve (reduce damage) each node by
  considering its precursors until no node
  improves.

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Initialization Enzymes
E2
R3
C5
E3
R4
R1
C2
C3
R2
E1
C4
T, 3
E1 E2 E3
F, 0 F, 0

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Initialization Reactions
E2
R3
C5
E3
R4
R1
C2
C3
R2
E1
C4
E1, T, 3
R1 R2 R3 R4
T, 3
E1 E2 E3
E1, T, 3

F, 0 F, 0

E2, F, 0
E3, F, 0
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Initialization Compounds
E2
R3
C5
E3
R4
R1
C2
C3
R2
E1
C4
E1, T, 3
C1 C2 C3 C4 C5
E1, T, 3
R1 R2 R3 R4
T, 3
E1, T, 3 E1, T, 3 E1, T, 3
E1 E2 E3
E1, T, 3

F, 0 F, 0


E2, F, 0
E3, F, 0
E2, E3, T, 1
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Iterations Reactions
E2
R3
R1 minR1, C5 min3, 1
C5
E3
R4
R1
C2
E2, E3, T, 1
R1 R2 R3 R4

C3
R2
E1
C4
E1, T, 3
C1 C2 C3 C4 C5
T, 3
E1, T, 3 E1, T, 3 E1, T, 3
E1 E2 E3
F, 0 F, 0


E2, E3, T, 1
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Iterations Compounds
E2
R3
C1 minC1, R1 min3, 1
C5
E3
R4
R1
C2
C3
R2
E1
C4
E1, T, 3
C1 C2 C3 C4 C5
T, 3
E1, T, 3 E1, T, 3 E1, T, 3
E1 E2 E3
F, 0 F, 0


E2, E3, T, 1
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How many iterations?
Number of iterations is at most the number of
reactions on the longest path that traverses each
node at most one
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Experiments Datasets
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Experiments Accuracy

• Average damage for one, two, and four randomly
  selected target compounds
• 10 10 10 runs for each network

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Experiments Running Time
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Experiments Number of Iterations