Teaching plan for the course unit

 

 

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General information

 

Course unit name: Design and Evaluation of Bioactive Molecules

Course unit code: 361584

Academic year: 2020-2021

Coordinator: Eva Estebanez Perpińa

Department: Department of Biochemistry and Molecular Biomedicine

Credits: 6

Single program: S

 

 

Estimated learning time

Total number of hours 150

 

Face-to-face and/or online activities

42

 

-  Lecture

Face-to-face

 

24

 

-  Group tutorial

Online

 

2

 

-  Problem-solving class

Online

 

8

 

-  IT-based class

Online

 

4

 

-  Student presentation and discussion

Online

 

4

Supervised project

50

Independent learning

58

 

 

Learning objectives

 

Referring to knowledge

— Learn basic and advanced guidelines in academia and the pharmaceutical sector on the selection of drug targets, the design of new drugs and the procedures for real-life drug discovery settings.

 

Referring to abilities, skills

— Become competitive doctoral students and postdoctoral fellows as well as practising scientists in academia and the pharmaceutical sector.

— Learn to display and analyse data and to present findings at international conferences.

— Learn to evaluate scientific projects and to leverage drug discovery ideas for real-life applications.

 

 

Teaching blocks

 

1. General introduction

1.1. Drug discovery, medicinal chemistry, translational medicine and patient-tailored medicine: relevance and applications in biomedicine

1.2. The evolution of drug discovery; Approaches to drug discovery; Real-world drug discovery; Potential and bottlenecks

2. Can drugs be designed?

2.1. What is rational drug discovery and what is not?

3. General introduction to target identification

3.1. Target discovery process; What is druggable? Is it the same for academic groups and pharmaceutical companies? Implications

4. Biomedical and economic implications of drug discovery

4.1. Are medical needs aligned with the health business? What are the main macromolecular pharmaceutical leads? Why?

5. Structural biology and bioinformatics in drug design

5.1. Opportunities and challenges for target identification and lead discovery: a structural biology view or a chemical view of target druggability

6. From virtuality to reality

6.1. Drugs: from discovery to approval; Hit-to-lead; Target identification, lead identification, lead optimisation steps and techniques

7. Chemical space and development of novel drugs for biomedicine

7.1. Are all chemical compounds potential drugs? Drug-like properties; What are pharmacophores? What compounds are bioavailable? In silico prediction of drug properties; Early-phase drug discovery: cheminformatics and computational techniques in identifying lead series

8. Brief review of the principles of protein and nucleic acid structure

8.1. Secondary, tertiary and quaternary structures relevant to the following topics; What are protein-protein and protein-DNA interactions?

9. Overview of biochemical and biophysical techniques for studying the structure and function of macromolecules

9.1. Relevance in drug discovery; Experimental vs. computational techniques; Why the fusion of the two techniques would yield the best results in drug discovery; Uses and limitations of each technique

10. Introduction to families of macromolecules most commonly targeted by major pharmaceutical companies and key targeted diseases

10.1. Description of GPCRs, nuclear receptors and the kinase family of proteins; Description of major antibiotics and their targets; Description of anti-cancer drugs: applications and drawbacks; Why do we still need novel drugs for major diseases? Side-effects and need for drug-discovery and how to bypass bottlenecks; Strategies for efficient drug discovery

11. Introduction to macromolecular leads not yet pursued as mainstream pharmaceutical targets

11.1. Protein-protein interactions as lead targets; Conformational trapping and targeting macromolecular complexes; Allosteric modulators; Minority diseases and their targets; Orphan drugs

12. Virtual screening in drug discovery

12.1. Overall description of scope and limitations; Current strategies for virtual screening; Development of reliable pharmacophores; Docking, scoring and visual inspection; Virtual screening as a routine tool? Protein plasticity: how to hit a mobile target; Rigid vs. flexible docking; Which computational approaches work best? How do they compare?

13. Compound and hit suitability for virtual screening

13.1. Compound selection and available libraries (open-access vs. proprietary); The role of leads in drug discovery; Compound processing prior to screening; Data mining approaches; Scoring functions and evaluation of binding between molecules and macromolecular targets

14. Fragment-based drug discovery: smaller is better?

14.1. Fragment-based high-throughput docking; Generation of ligand conformations; Binding site search and definition; Role of conserved water molecules

15. Structure-based drug discovery

15.1. Use of X-ray crystallography and NMR; Detection of novel (allosteric) sites; Targeting protein-protein interactions; Use of synchrotrons in drug discovery; High-throughput crystallography for lead discovery in drug design; Limitations and lessons in the use of X-ray structural information in drug design

16. From laptop to benchtop to bedside

16.1. Stages of clinical development of novel drugs; FDA and other regulatory agencies; Security checkpoints; What are clinical trials?

17. Case studies and drug discovery: biomedical applications

17.1. Evolution of pharmaceutical ligands; Implications for CNS pathologies, metabolic syndrome, auto-immune disease, tumour development, etc.

Examples: GPCRs; Protein kinases; Proteases; Nuclear receptors; Epigenetic targets; Oncology, anti-tumoral drugs; Protein-protein interactions; Allosteric modulators

18. Unless the requirements enforced by health authorities demand a prioritisation or reduction of these contents

 

 

Teaching methods and general organization

 

The methodology includes lectures, talks by guest speakers (leading figures in drug discovery fields in academia and the pharmaceutical sector), field trips to laboratories and pharmaceutical platforms.

The proposed teaching methodology may experience some modifications depending on the restrictions to face-to-face activities enforced by health authorities.

 

 

Official assessment of learning outcomes

 

— Regular training and oral presentations (individual and in groups) on topics assigned by the lecturer; preparation of talks on an area of drug discovery chosen by the student (worth 50% of the final grade). 

— Active participation in class and sessions by guest speakers. This includes short tests done in class (50%).

 

Examination-based assessment

— Regular training and oral presentations (individual and in groups) on topics assigned by the lecturer; preparation of talks on an area of drug discovery chosen by the student (worth 50% of the final grade). 

— Active participation in class and sessions by guest speakers. This includes short tests done in class (50%).

Students’ assessment may experience some modifications depending on the restrictions to face-to-face activities enforced by health authorities.

 

 

Reading and study resources

Consulteu la disponibilitat a CERCABIB

Article

BLUNDELL, T.L. ;PATEL, S. High-throughput X-ray crystallography for drug discovery. Dins: Current Opinion in Pharmacology [en línia]. 2004 Oct;4(5):490-6  EnllaƧ

BLUNDELL, T.L. ; JHOTI, H. ; ABELL, C. High-throughput crystallography for lead discovery in drug design. Dins: Nature Reviews Drug Discovery [en línia]. 1, 45-54 (Jan 2002)  EnllaƧ

CONGREVE, M. ; MURRAY, C.W. ; BLUNDELL, T.L. Structural biology and drug discovery. Dins: Drug Discovery Today [en línia]. 2005 Jul 1;10(13):895-907  EnllaƧ

EGNER, U. (et al.). The target discovery process. Dins: Chembiochem [en línia]. 2005 Mar;6(3):468-79  EnllaƧ

BLUNDELL, T.L. (et al.). Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery. Dins: Philosophical transactions of the Royal Society of London. Series B, Biological sciences  [en línia]. 2006 Mar 29;361(1467):413-23  EnllaƧ

JUBB, H. ; HIGUERUELO, A.P. ; WINTER, A. ; BLUNDELL, T.L. Structural biology and drug discovery for protein-protein interactions. Dins: Trends in pharmacological sciences [en línia]. 2012 May ; 33(5):241-8. doi:10.1016/j.tips.201203.006  EnllaƧ

SURADE, S. ; BLUNDELL, T.L. Structural biology and drug discovery of difficult targets: the limits of ligandability. Dins: Chemistry and Biology [en línia]. 2012 Jan 27;19(1):42-50. doi: 10.1016/j.chembiol.2011.12.013  EnllaƧ

MURRAY, C.W. ; BLUNDELL, T.L. Structural biology in fragment-based drug design. Dins: Current opinion in structural biology [en línia]. 2010 Aug;20(4):497-507. doi: 10.1016/j.sbi.2010.04.003  EnllaƧ

EGNER, U. (et al.). Different ligands-different receptor conformations: modeling of the hER alpha LBD in complex with agonists and antagonists. Dins: Medicinal research reviews [en línia]. 2001 Nov;21(6):523-39  EnllaƧ