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BIOMD0000000561 - Martins2013 - True and apparent inhibition of amyloid fribril formation

 

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Reference Publication
Publication ID: 23232498
Martins PM.
True and apparent inhibition of amyloid fibril formation.
Prion 2013 Mar-Apr; 7(2): 136-139
ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal. pmmartins@icbas.up.pt  [more]
Model
Original Model: BIOMD0000000561.origin
Submitter: Audald Lloret i Villas
Submission ID: MODEL1412110000
Submission Date: 11 Dec 2014 15:28:29 UTC
Last Modification Date: 08 Apr 2016 18:52:20 UTC
Creation Date: 11 Dec 2014 15:30:21 UTC
Encoders:  Audald Lloret i Villas
set #1
bqmodel:isDerivedFrom BioModels Database Crespo2012 - Kinetics of Amyloid Fibril Formation
set #2
bqbiol:hasTaxon Taxonomy Homo sapiens
set #3
bqbiol:isVersionOf Gene Ontology amyloid fibril formation
set #4
bqbiol:hasProperty Human Disease Ontology Alzheimer's disease
Human Disease Ontology DOID:14330
Human Disease Ontology prion disease
Notes
Martins2013 - True and apparent inhibition of amyloid fribril formation

This model is described in the article:

Martins PM.
Prion 2013 Mar-Apr; 7(2): 136-139

Abstract:

A possible therapeutic strategy for amyloid diseases involves the use of small molecule compounds to inhibit protein assembly into insoluble aggregates. According to the recently proposed Crystallization-Like Model, the kinetics of amyloid fibrillization can be retarded by decreasing the frequency of new fibril formation or by decreasing the elongation rate of existing fibrils. To the compounds that affect the nucleation and/or the growth steps we call true inhibitors. An apparent inhibition mechanism may however result from the alteration of thermodynamic properties such as the solubility of the amyloidogenic protein. Apparent inhibitors markedly influence protein aggregation kinetics measured in vitro, yet they are likely to lead to disappointing results when tested in vivo. This is because cells and tissues media are in general much more buffered against small variations in composition than the solutions prepared in lab. Here we show how to discriminate between true and apparent inhibition mechanisms from experimental data on protein aggregation kinetics. The goal is to be able to identify false positives much earlier during the drug development process.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 23232498 Submission Date: 11 Dec 2014 15:28:29 UTC Last Modification Date: 08 Apr 2016 18:52:20 UTC Creation Date: 11 Dec 2014 15:30:21 UTC
Mathematical expressions
Rules
Assignment Rule (variable: gamma) Assignment Rule (variable: deltamt) Assignment Rule (variable: Amyloid)  
Physical entities
Compartments Species
Brain Amyloid    
Global parameters
kb ka sigmao V
C* gamma deltamt C
Reactions (0)
Rules (3)
 
 Assignment Rule (name: gamma) gamma = (C_0-C)/C
 
 Assignment Rule (name: deltamt) deltamt = sigmao*V*C*gamma
 
 Assignment Rule (name: Amyloid) Amyloid = (1-1/(kb*(exp(ka*time)-1)+1))*deltamt
 
 Brain Spatial dimensions: 3.0  Compartment size: 1.0
 
  Amyloid
Compartment: Brain
Initial concentration: 0.0
 
Global Parameters (8)
 
 kb
Value: 0.001
Constant
 
 ka
Value: 0.5
Constant
 
 sigmao
Value: 1.0
Constant
 
 V
Value: 1.0
Constant
 
 C*
Value: 1.0
Constant
 
  gamma
Value: 1.0
 
  deltamt
Value: 1.0
 
   C
Value: 2.0
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000561

Curator's comment: (updated: 11 Dec 2014 15:36:40 GMT)

Figure 1a of the reference publication has been reproduced here: Inhibition of amyloid fibrillization as predicted by the Crystallization-like model (CLM) for sigmoidal aggregation kinetics.
Black curve represent the normalized fibril mass increase as a function of time (20 arbitrary units). Blue and red curves represent the inhibition of the nucleation and growth steps (true inhibition), respectively; green curve represent the apparent inhibition. The variation of parameters relatively to the normalized mass increase is indicated in the legend.

The simulation was done using Copasi v4.14 (Build 89) and the plots were generated using Gnuplot. The Copasi file of the model with simulation settings can be downloaded from the below link:

Additional file(s)
  • Martins2013 - True and apparent inhibition of amyloid fribril formation:
    Copasi file of the model
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