AuthorsC2TN members: Rita Melo1,*, Sandra Cabo Verde3, João D. G. Correia1

Research group(s) CollaborationsCenter for Neuroscience and Cell Biology|

Coimbra, Portugal

iMED| Research Institute for Medicines,

Faculty of Pharmacy, UL, Lisboa, Portugal

Icahn School of Medicine| Department of Genetics and Genomics and Icahn Institute for Genomics and Multiscale Biology at

Mount Sinai, New York, USA

Thematic StrandRadiopharmaceutical Sciences & Health Physics

Funding

Molecular modelling in drug development and VLP design

IntroductionIncreasing insights into the genetics and molecular biology of diseases has resulted in the identification of an high number of potential molecular targets fordrug discovery and development. Also, nanomedicine emerged as a new field created by the fusion of nanotechnology and medicine, and is currently one ofthe most promising approaches for the development of effective targeted therapies. Molecular modelling can be used to bring new perspectives, both instructure-based drug design and in providing information at nanoscale of new platforms via interactive computational methods. Currently, we are focusing onthe design of virus-like particles (VLPs) as theranostic tools for HER2-positive cancer cells. Besides that, we are also interested in the development of newmolecular modelling tools for drug design and their application to neurodegenerative diseases mechanistic understanding and treatment. We believe thatfuture research breakthroughs with aid of computer-aided molecular design and chemo-bioinformatics will allow a more comprehensive perception onbiomedicine.

Drug design – Central Nervous System Virus-Like particles

Conclusions and Perspectives• We have developed a novel multidisciplinary structural biochemistry approach combining computational and experimental methods to

investigate VLPs at the nanoscale• The HER2-binding properties and theranostic potential of the modified VLPs will be evaluated after radiolabeling followed by biological

assessment in specific cancer lines and animal models.• Increase the potentialities of computational methods on drug design & development: exploitation of new targets

Publications1- Lemos, A.; Melo, R.; Moreira, I. S.; Cordeiro, M. N. D. S., Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease. In Computational Modeling of Drugs Against Alzheimer’s Disease, Roy, K., Ed. Springer New York: New York, NY, 2018; pp 61-106.2- Moreira, I. S.; Koukos, P. I.; Melo, R.; Almeida, J. G.; Preto, A. J.; Schaarschmidt, J.; Trellet, M.; Gümüş, Z. H.; Costa, J.; Bonvin, A. M. J. J., SpotOn: High Accuracy Identification of Protein-Protein Interface Hot-Spots. Scientific Reports 2017, 7 (1), 8007.3- Lemos, A.; Melo, R., Preto, A.J.; Almeida, J.G.; Moreira, I.S.; Cordeiro, M. Natália D. S., In silico approaches for Parkinson drug development targeting G-protein coupled receptors, 2018, in press Current Neuropharmacology4- Melo, R., Fieldhouse, R., Melo, A., Correia, J. D. G., Cordeiro, M. N. D. S., Gümüs, Z. H., … Moreira, I. S. (2016). A Machine Learning Approach for Hot-Spot Detection at Protein-Protein Interfaces. International Journal of Molecular Sciences, 17(8), 1215. 5- Almeida, J.; Preto, A.; Melo, R.; Gümüs, Z.; Costa, J.; Bonvin, A.; Moreira, I. Co-evolution importance on binding Hot-Spot prediction methods. In Proceedings of the MOL2NET, International Conference on Multidisciplinary Sciences, 25 December 2016–25 January 2017; Sciforum Electronic Conference Series, Vol. 2, 2017

Receptor HER2

scFv fromTrastuzumab

ECDI

ECDII

ECDIII

ECDIVMolecular Dynamics: two

replica, 0.5 s/each; GROMACS 5.0.4 conjugated with the

Amber99 force field.

Drug designMolecular modelling

NanomedicineTheranostics

Virus-like particles

Keywords

Essential Dynamics analysis: eigenvectors

Membrane construction: The complex system is being studied in conjugation to gp41 (structure optimized by modeling) in the lipid bilayer CHOL(2):POPC(20):POPA(15) constructed using the CHARMMGUI server.

Solvent-Accessible Surface Area (SASA)Heatmap of distances betweeninterfacial residues

scFv from Trastuzumab HER2

H-Bonds

scFv from Trastuzumab HER2

(C) Complex between mGluR5 and mavoglurant(PDB entry 4OO9)

In silico studies in the drug research against Parkinson’s disease (PD)

(A) Complex between GPCR (A2AAR) and ZM241385 (PDB entry 3EML)

(B) Complex between mAChR1 and tiotropium(PDB entry 5CXV)

Signaling cascade of the distinct subtypes of GPCRs potentially involved in PD

• identification of hotspots• description of biological system

with all-atom detail

1 RS | Radiopharmaceutical Sciences Group2 RPS | Radiation Protection and Safety Group3 REI | Radiation, Elements and Isotopes Group4 NET | Nuclear Engineering and Techniques Group5 QEf | f-element Chemistry Group6 SS | Solid State Group

http://c2tn.tecnico.ulisboa.ptRADIATION FOR SCIENCE AND SOCIETY

C2TN/IST acknowledgesFundação para a Ciência e a Tecnologia for

financial support under the projectUID/Multi/04349/2013

* Email of corresponding author: ritamelo@ctn.tecnico.ulisboa.pt