Biomolecular Characterization for Rational Drug Design. Maria João Romão

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1 Biomolecular Characterization for Rational Drug Design Maria João Romão Applied Molecular Biosciences Unit Chemistry Department - FCT NOVA mjr@fct.unl.pt / CIÊNCIA th July 2015

2 UCIBIO Applied Molecular Biosciences Unit Host Institution Unidade de Ciências Biomoleculares Aplicadas UID/Multi/04378/2013 Laboratório Associado para a Química Verde

3 UCIBIO Applied Molecular Biosciences Unit Multidisciplinary Unit Chemists, Biochemists, Biologists, Pharmacists &Toxicologists 128 Integrated members 151 PhD Students Funding ( ) Total 25.2 M Scientific Output ( ): 1416 Index publications 123 PhD awarded 20 Patents Industry funding 3.3 EC funding 1.7 Pluriannual Programme 3.9 Other funding 4.1 FCT funding 8.7 COMPETE 3.7 Several prizes:

4 Internationalization /Funding Europe USA Brasil Angola

5 Mission and Structure Mission Statement - Broad scope of fundamental and applied research at the interface of Chemistry and Biology to address pertinent questions at atomic, molecular, sub-cellular and cellular levels

6 Advancement of knowledge at the cutting edge of Biomolecular Sciences Atomic Level Drug Discovery Molecular Level Safety Assessment for Health & Environment Functional (Nano)molecules for Diagnosis & Therapeutics Cellular & sub-cellular Level Mechanisms of Drug Resistance Integrative & interdisciplinary approach to address major societal challenges Molecular Epidemiology & Adaptation Spin-off / Companies

7 Mission and Structure THEMATIC LINES 1. Biomolecular Interactions 2. Drug Discovery 3. Safety Assessment in Human & Environmental Health 4. Molecular Diagnosis & Therapeutic Research Groups Chem4Omics Functional Molecules & Nanomaterials Structural Molecular Biology Molecular Microbiology Theoretical & Computational Biochemistry Toxicology Drugs Targets & Biomarkers Biomodels, Bioanalytics and Biophysics

8 Thematic Line Drug Discovery Design, synthesis, screening of Functional compounds Molecules & Nanomaterials Structure-based Theoretical & & rational DD Structural Computational Molecular Biochemistry Biology in vivo/in vitro studies Drugs Targets & Biomarkers Drug Discovery Toxicology Efficacy and safety of novel compounds Biomodels, Bioanalytics Biophysics Molecular docking, virtual screening, QSAR Design & characterization of nanosystems

9 Biomolecular Characterization for Rational Drug Design Biophysical/Bioche mical Characterization Protein Structure and Dynamics Protein-Protein and Protein-Ligand interactions Thermodynamics X-ray Crystallography Advanced Spectroscopies (NMR, CD, ) High Throughput Screening (ITC, Glycoarrays ) Computational Biochemistry Target Functional and Structural Characterization Structure Activity Relationships Hit discovery and Lead Optimization New targets New compounds

10 Biomolecular Characterization for Rational Drug Design Integrated Structural Biology Platform Portuguese Roadmap of RI - NMR Network (coordination) ESFRI RI - MS Network NMR, Xray-Crystallography, BioSAXS, MS, Protein production, HTP screening, Advanced Biophysical Methods, Computer Cluster Facility Cell cultures and Animal facilities Analytical, (Bio)Chemistry,

11 RECIPE FOR DESIGNING DRUGS THAT MIMIC THE TS 1. Establish the enzymatic catalytic mechanism; MJ Ramos

12 1. Establish the enzymatic catalytic mechanism MJ Ramos Regulation of tumorogenesis NADP+ reduction by the isocitrate substrate with the help of K212B ISOCITRATE DEHYDROGENASE Neves, Fernandes, Ramos, ACS Catalysis, 2016, 6,

13 RECIPE FOR DESIGNING DRUGS THAT MIMIC THE TS 1. Establish the enzymatic catalytic mechanism; 2. Find out the geometry of the transition state (TS) of the rate limiting step of the reaction; MJ Ramos

14 2. Find out the geometry of the transition state (TS) Transition state (TS) ΔG / kcal.mol -1 Enzymes stabilize the TS more than the reactants MJ Ramos reaction coordinate

15 RECIPE FOR DESIGNING DRUGS THAT MIMIC THE TS 1. Establish the enzymatic catalytic mechanism; 2. Find out the geometry of the transition state (TS) of the rate limiting step of the reaction; 3. Enzymes stabilize the TS more than they stabilize the reactants and therefore model the geometry of the inhibitor on the geometry TS. MJ Ramos

16 Human Aldehyde Oxidase - Impact In Drug Metabolism haox1 active haox1 active drugs, xenobiotics Substrate drugs, xenobiotics I inactive I inactive Inhibition Mo Inhibitor Mo X-ray structure Nat Chem Biol, 2015 Nature Chem Biol, 2015 Importance in drug and xenobiotic metabolism Inter-species differences unsuitable animal models Impact: X-ray Structure & Computational prediction of better drugs - Development of novel metabolism-resistant drugs - Less failures in clinical trials Coelho, Romão et al, JBC, 2012 Coelho, Santos-Silva, Romão et al, NCB, 2015 CDA with

17 Anti-Glycan Antibodies Impact in Cancer Therapy Target: Monoclonal antibodies to tumor-associated glycan antigens Lec ns Glycan microarrays Therapeu c an bodies X-Ray Altered glycosylation (TACA) is a hallmark of cancer and is immunesuppressive Lec ns Glycan microarrays Therapeu c Antibodies to glycansan bodies target cancer cells and re-engage the immune system Glycan microarrays Lec ns Glycan microarrays X-Ray Therapeu c Therapeu an bodies c Molecular Modeling an bodies STD-NMR NMR STD-NMR Molecular Modeling STD-NMR Glycobiology Impact: Identification of key structure-features of antibody-antigen recognition Molecular Modeling Production of therapeutic antibodies with high specificity and efficacy STD-NMR NMR Development of better anti-cancer vaccines (e.g. dendritic cells) Coelho HJ, Marcelo F, et al JACS, 2015 Palma A et al, Curr Op Chem Biol, 2014 P. Videira

18 Drug Discovery Chemistry: Design, synthesis and characterization of novel molecules Structural Biology: determination of 3D structures of target proteins and structural mapping of protein-protein and protein-ligand interactions. Computational Sciences: Structure-based and rational DD and clarification of enzymatic mechanisms crucial to fully characterize the target of interest. Toxicology: in vitro and in vivo studies for pre-clinical evaluation of efficacy and safety of novel structures Discovery and validation of new genetic, biochemical and cellular markers with potential applications in development of new drugs Screening: Novel bioanalytical methods high-throughput and screening methods.

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