Molecular modelling in drug development and VLP...
19
Molecular modelling in drug development and VLP design Rita Paiva de Melo, Post Doc Radiopharmaceutical Sciences Group [email protected] C 2 TN-RADIATION FOR SCIENCE AND SOCIETY: 1 ST WORKSHOP 6 TH DECEMBER 2017
Transcript of Molecular modelling in drug development and VLP...
Molecular modelling in drug development and VLP design Rita Paiva de Melo, Post Doc
Radiopharmaceutical Sciences Group
C2TN-RADIATION FOR SCIENCE AND SOCIETY: 1ST WORKSHOP 6TH DECEMBER 2017
Background and Motivation
Why is Molecular Modeling Important?
• 3D structure of a protein is essential for understanding the details of its molecular function and gives valuable insights for the development of effective rational strategies for experiments
• Rapid discovery of new drugs
• The most useful models are those originated by a synergy between computational and experimental efforts HIV-1 Capsid Structure
Background and Motivation
Background and Motivation SOCIETAL IMPACT
HER2 positive breast cancer: aggressiveness, drug resistance
RESEARCH HYPOTHESIS
The synergy between computational and experimental has greatly benefited both fields. Use the well-known targeted therapies to develop a new strategy to downstream HER2
pathways
OBJECTIVE
Develop of a nanoplatform to target specifically HER2
Background and Motivation
In: Chou et al, Chem Soc Rev, 2011, 40, 233-245
Theranostic nanoparticles give the best of both worlds
Background and Motivation
Reproduced from M. Ferrari, “Cancer nanotechnology: opportunities and challenges,” Nature Reviews Cancer, vol. 5, no. 3, pp. 161–171, 2005.
Target specific delivery of imaging agents and/or anticancer agents
Therapeutic agents
Enhanced permeability and retention (EPR) effect
Adapted from: Peer et al, Nature Nanotechnology, 2007, 2, 751-760
nanoparticle
Background and Motivation
• VLPs are look-alikes of infectious virions containing “empty shells”
• VLPs lack viral genome and therefore are non-pathogenic
Virus-like particles
Objective HIV-based VLP
Anti-HER2 single chain variable fragment (scFv)
Model of VLP interaction with HER2
Results
HER2 extracelular domains scFv from Trastuzumab
REAL SYSTEM MAKE A MODEL MODEL SYSTEM
Methods Software
Homology Modeling
ModBase
Hotspots prediction
SpotOn
Computational chemistry
Results REAL
SYSTEM MAKE A MODEL
MODEL SYSTEM
PERFORM SIMULATIONS
SIMULATION RESULTS
• Identification of hotspots • Heatmap of distances between interfacial
residues • Solvent-Accessible Surface Area (SASA) • H-Bonds
Methods Software
Molecular Dynamics GROMACS
An
alys
is
Normal Mode Analysis
R (bio3d package) Principal component analysis
Conservation ConSurf
Distance, SASA, HBonds In house scripts
Methods Software
Molecular docking HADDOCK webserver
Results
Results
Methods Software
Membrane construction CHARMMGUI server
REAL SYSTEM MAKE A MODEL MODEL SYSTEM
PERFORM EXPERIMENTS
EXPERIMENTAL RESULTS
PERFORM SIMULATIONS
SIMULATION RESULTS
COMPARE AND IMPROVE MODEL
Perspectives
C2TN-RADIATION FOR SCIENCE AND SOCIETY
Optimization of nanoplatforms for theranostic applications Application of computationtal tools to improve networking in topics related to drug design: • in silico screening of peptide-based molecules towards disruption of protein-protein
interactions relevant for drug development and design
• Machine learning methods to increase the traceability of receptors that are involved in biological pathways
Strategy
C2TN-RADIATION FOR SCIENCE AND SOCIETY
Rita Melo, post-doc 2 MSc students (computational and medicinal chemistry)
Luis Costa Lab, IMM
Irina S. Moreira, CNC, Coimbra Portugal
Zeynep Gumus, Icahn School of Medicine at Mount Sinai, USA
Alexander Bonvin, Utrech University, Netherlands
João Gonçalves, iMed, FFUL/UL
Human Resources
Collaborations
C2TN-RADIATION FOR SCIENCE AND SOCIETY
- Innovative HIV-based VLPs for theranostics applications
- Versatile platforms for various applications in different topics
- Small team - Low budget
- R&D capabilities: both computational and experimental - Well-implemented network - infrastructures
- Low budget - Human
resources uncertainty
Molecular modelling in drug development and VLP design Rita Paiva de Melo, Post Doc
Radiopharmaceutical Sciences Group
C2TN-RADIATION FOR SCIENCE AND SOCIETY: 1ST WORKSHOP 6TH DECEMBER 2017
