Syllabus
1. General information – aims of the lecture series, topics covered; Intro – past and recent approaches to drug discovery; Time- and price scale of drug discovery projects.
2. Drug-like properties and druggable targets – definitions; molecular properties and drug-likeness, molecular descriptors (Lipinski, MPO...), chemical spaces; Drug targets – (non)druggable targets, druggability, link to chemical space.
3. In vitro Pharmacology – types of biochemical (in vitro) assays, biochemical vs. functional (phenotypic) assays, main classes of molecular targets: enzymes (inhibitions modes, assay types, enzyme coupled assays), receptors (binding vs. Functional assay, FRET, GPCRs…), ion channels,…; phenotypic (functional) assays – use, advantages and limitations, examples (penicillin, antifungals…); High throughput screening, well-plate assays, libraries.
4. In vitro pharmacokinetics – definition, DMPK, ADME(Tox); what happens to the drug in organism; importance of in vitro PK in drug discovery (historical comparison); main methods of in vitro PK: absorption (CaCo2 and others, passive vs. active transport, BBB), metabolism (liver microsomes, cytochrome P450, inhibition/induction of metabolism, phase I and phase II, toxicity of acetaminophen, interspecies differences), plasma protein binding (HSA/AAG, effect on bioavailability).
5. In vivo Pharmacokinetics – in vitro-in vivo PK relationship, what happens to the drug in organism (repeated); blood (plasma) as central compartment, animal species used in different stages of the project; administration methods; sampling and blood sample processing; sample analysis (LC/MS/MS); pharmacokinetic parameters (AUC, Vd, T1/2, Cl, Vmax, Tmax, % F) and desired values for successful drug; 1- and 2- compartment PK models; dosing (in)dependent parameters; distribution of drug between blood and tissues (limits of B/P analysis).
6. In vivo Pharmacology – definition and interconnection with other drug discovery disciplines; Law and ethics (the rule of „3 R"); historical perspective; possibilities, limits and alternatives of animal disease models; basic aspects of planning the in vivo study (species, gender, age, dosing...); different types of in vivo disease models ("easy" vs "tough," spontaneous vs induced – genetic, physical, chemical, xenografts) and evaluation of efficacy; example 1: Parkinson’s disease (chemical induction); example 2: Huntington’s disease (genetic induction); example 3: "cancer" (xenograft).
7. Intellectual property/Patent law – what is patent and its importance in drug discovery, different types of patent applications, requirements of patentability, patent application process, priority date, timeline of patenting process, length of protection, generics...
8. Medicinal chemistry: the glue of drug discovery (flow chart); multiparameter optimization of molecular properties, historical vs modern approaches, SAR, fragment-based screening, hit to lead, lead optimization, pharmacophores, bio isosteres, solubility, PAINS, prodrugs (theory)...
9. Medicinal chemistry: synthetic methods and approaches in „drug discovery“ („buy what’s available); peptide couplings, transition metal catalysis, common protective groups; combinatorial chemistry; analytical methods (LCMS for reaction monitoring); isolation and purification of products (simple and fast).
10. 1-2 drug discovery case studies (selection from following: retrovirostatics – IOCB/Gilead Holy trinity, Penicillin – historical approach, Captopril – modern approach).
11. Biologics: definition, biologics vs small molecules: (dis)advantages, types of biologics, monoclonal antibodies, antibody-drug conjugates. Exam.
Annotation
The main focus of the lecture series is to share an overview of basic knowledge necessary for participation in multidisciplinary projects focused on drug discovery. The lectures are not focused on in-depth analysis but rather on brief introduction to the topics in friendly atmosphere.
We will start with general information and introduction to the paradigm of target-based drug discovery. Subsequently, main drug discovery topics and disciplines will be introduced in the approximate order of their involvement in hypothetical project.
Discussed topics will encompass properties of molecules as drug candidates, description and properties of different classes of drug targets, types of in vitro and in vivo assays necessary to evaluate drug candidates and desirable range of drug properties described by these assays, animal models of human diseases, methods used in drug candidate optimization, synthetic methods used in drug discovery as well as IP protection. The lecture series will not cover clinical evaluation of drug candidates.