NETWORK-BASED TARGET RANKING FOR POLYPHARMACOLOGICAL THERAPIES

Francesca Vitali, Francesca Mulas, Pietro Marini and Riccardo Bellazzi

University of Pavia, Italy

Drug Discovery

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Drug Discovery Today

Decline in: Clinical development Productivity

Standard approach

MAGIC BULLET
SINGLE TARGET DRUGS

Emerging approach
Angelo Nuzzo
IIT@SEMM, Milan, 2011

POLYPHARMACOLOGY

Polypharmacology
MULTI TARGET DRUGS
Collective weak interactions vs single strong interaction

Improve therapeutic efficacy - Multi-factorial diseases (e.g. cancer)

Avoid - Adaptive drug resistance
Protein

Drug

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Network-based Polypharmacology
Prior knowledge on complex diseases

DATA SOURCES + PROTEIN INTERACTION NETWORKS

Interaction Protein
Angelo Nuzzo
IIT@SEMM, Milan, 2011

Method
Disease of interest

Network design

Network targeting

Scoring of target combinations

Ad hoc analysis of drug agents related to the selected targets

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Method
Disease of interest
Type 2 Diabetes Mellitus (T2DM)

Network design

Network targeting

Scoring of target combinations

Ad hoc analysis of drug agents related to the selected targets

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Method
Disease of interest

Network design

Network targeting

Scoring of target combinations

Ad hoc analysis of drug agents related to the selected targets

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Network design
Human proteins involved T2DM pathways Network

Protein Protein Interaction Repository

NODES Proteins

EDGES Interactions

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Biological Network Features

Interactions Experimental evidence - Not considering: Literature mining, co-occurence, ecc. Confidence Score 0.7 (high confidence)

NODES 587 EDGES 3683

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Disease Network
Diabetes vs control Up- and downregulated genes

87 disease proteins

Network genes

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Method
Disease of interest

Network design

Network targeting

Scoring of target combinations

Ad hoc analysis of drug agents related to the selected targets

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Network Targeting

Node constraints: Druggable Not Hub High Bridging Centrality

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Druggability

DRUG INTERACTIONS

Chemical Protein Interaction Repository

LOCALIZATION

Cell membrane Extracellular space

DRUGGABLE PROTEINS 206 + 108

Angelo Nuzzo
IIT@SEMM, Milan, 2011

Hub
Hub
1. High # neighbours 2. Located between highly connected regions Traditional pharmacology DISCARDED AS POTENTIAL POLYPHARMACOLOGICAL TARGET
DISCARDED HUB 14

Hub discovery method:

Vallabhajosyula et al. Identifying hubs in protein interaction networks.

PLoS ONE, 4(4):e5344, 2009.

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Bridging Centrality
Bridging centrality

BC = Bridging Coefficient

RWB = Random-walk Betweenness

Bridging Coefficient Local bridging properties Penalizes hub

Betweenness centrality Global bridging properties Influence of a node in the spread of information through the network

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Bridging Centrality
Bridging centrality

BC = Bridging Coefficient

RWB = Random-walk Betweenness

Bridge node first 25% of the nodes ordered by bridging centrality
Hwang et al. Bridging centrality: Identifying bridging nodes in scale-free networks. Knowledge Discovery and Data mining, 2006

BRIDGING PROTEINS 147

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Target selection

Druggable Non hub Bridge nodes

47 target proteins

Sources of pharmacological actions

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Method
Disease of interest

Network design

Network targeting

Scoring of target combinations

Ad hoc analysis of drug agents related to the selected targets

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Drug Synergy
Reachability of a single Disease Protein i Wi,j j

T
Sh = shortest path

w i,j = edge weight between

(i,j) = node pair

i and j

Reachability of all DPs

Np = # disease proteins

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Drug Synergy

TRIPLETS

Low computational cost Upper limit to the number of drugs to be jointly delivered
Angelo Nuzzo
IIT@SEMM, Milan, 2011

TSDS
TSDS (Topological Score of Drug Synergy) of a triplet

Null distribution: TSDS for 50 000 triplets of proteins randomly selected from the network
88 triplets with Combinations of 18 targets P-Value < 0.01
Angelo Nuzzo
IIT@SEMM, Milan, 2011

TSDS

Method
Disease of interest

Network design

Network targeting

Scoring of target combinations

Ad hoc analysis of drug agents related to the selected targets

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Target Analysis
Frequency

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Target Analysis
Frequency

Insulin-like growth factor family

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Target Analysis
Frequency

EXPERIMENTAL EVIDENCE Negative regulator of insulin signalling TO BE INHIBITED Extract of Larrea Tridente 1. Decrease plasma glucose triglyceride concentrations 2. Inhibits IGF1R activity

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Target Analysis
Frequency

Alzheimer

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Target Analysis
Frequency

Alzheimer

Recent Studies

T2DM

Alzheimer
Strongly altered expression of Strongly altered IGF1R/IGF expression of IGF1R/IGF

Patients with T2DM have a 2- to 3-fold increased risk for AD.

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Target Analysis
Frequency

Only one standard target

Angelo Nuzzo

IIT@SEMM, Milan, 2011

Conclusion
Network-based method for feasible identification of multi-component synergy Data integration Topological feature analysis Scoring system

Results: Disease-causative pathways Potential multi-target nodes To discover new therapies To support the standard therapies
Future steps: Testing on other complex diseases Application to directed network

Angelo Nuzzo

IIT@SEMM, Milan, 2011

NETWORK-BASED TARGET RANKING FOR POLYPHARMACOLOGICAL THERAPIES

Thanks.