Synthetic Drugs Design

Course unit

title

Scientific direction

Scientific code

Faculty

Department (s)

Synthetic Drugs Design

Chemical Engineering, T005

Life Sciences Center

Institute of Biotechnology

Mode of studies

Number of credits

Mode of studies

Number of credits

Lectures

0

Consultations

1

Self-studies

6

Seminars

1

Aims of course

Synthetic drug design doctoral course aims to develop students’ independence, critical and analytical thinking and ability to present scientific information. Students will become acquainted with principles of synthetic drugs development starting with the search for an active compound and ending the active compound becoming a drug and entering the market.        

Main topics

Human being- diseases- drugs. The relationship between chemistry and medicine.

Drug binding. Covalent binding, electrostatic or ionic bonds, hydrogen bonds, hydrophobic interaction, Van der Walls interaction, the role of water in interactions.

Drug target- proteins. Enzymes, receptors, transport proteins.  

Enzymes. Interaction models: lock and key model, induced fit, conformational selection. Types of inhibitors: reversible- competitive, noncompetitive, uncompetitive, irreversible (e.g. suicide inhibitors), alosteric. Enzyme kinetics V_max, k _cat, K_M.  Binding affinity. The strength of the interaction (K_b, K_d, ΔG_b ). Enzymatic Activity Inhibition Assay. The potency of inhibitor (K_i, IC₅₀). Isozymes.

Receptors as Drug Targets. Types of receptors. Agonists, antagonists, alosteric antagonists, partial agonists, inverse agonists. The strategies for design of agonists and antagonists. Sensitization and desensitization. Affinity, efficacy, and potency.

Nucleic acids as drug targets. DNA as drug target, classification of active compounds. RNA as drug target, agents that bind to ribosomes, antisense therapy.  

Miscellaneous drug trgets- lipids, carbohydrates.

Bioassay. In vivo, ex vivo, in vitro, in silico tests.

The search of lead compound. Hit. From hit to lead. Skreening. HTS- high-throughput screening. Fragment screening. Screening methods: biophysical approaches, mass spectrometry, nuclear magnetic resonance (NMR) spectroscopy, crystallographic screening. Virtual screening. Early tests for potential toxicity. The strategies of the search of lead compound  (e.g. screening of natural sources, combinatorial synthesis, etc.). 

Lead compound optimization. Improvement of target interactions. The role of functional groups (e.g. amines, carboxylic acids, etc.) in optimization. Indentification of pharmacophore. Lead compound optimization strategies (e.g. ring variations, variation of substituents on aromatic or heteroaromatic rings, etc.). Isosteres and bioisosteres. Chirality. Improvement of access to the target. Optimization of ADME properties. Druglikeness. Lipinski's rule of five. Veber’s rules Optimizing hydrophilic/hydrophobic properties. Making drugs more resistant to chemical and enzymatic degradation. Strategies for reduction of toxicity. Prodrugs and their aplication (e.g. improvement of membrane permeability, prolongation of drug activity, etc.).

Pharmacokinetics. Absorption, distribution, metabolism, and excretion (ADME). The first pass effect- first-pass metabolism. Orally active drugs. Drug distribution. Pharmacokinetic parameters (e.g. clearance (Cl), half-life, bioavailability (F), etc.) Blood brain barrier. Drug metabolism (phase I, phase II). Phase I- oxidative reactions catalysed by cytochrome P450 enzymes on saturated carbon centres, amines, ethers, hetroatoms and unsaturated centres. Other important oxidative enzymes- alcohol dehydrogenases, aldehyde dehydrogenases, esterases, peptidases. Phase II (e.g. glucuronic acid conjugation, sulphate conjugation, methylation, etc.). Metabolic stability.

Computers in drug design. Docking. De Novo drug design. QSAR- quantitative structure-activity relationship. Physicochemical descriptors- hydrophobicity- the partition coefficient (P), the substituent hydrophobicity constant (π). Electronic descriptors- Hammett constant. Steric descriptors- Taft’s steric constant. Free-Wilson model. Hansch model. The Craig plot. The Topliss scheme. 3D QSAR.

Combinatorial and Parallel Synthesis.

Getting the Drug to Market. Patenting. Chemical development. Regulatory affairs. Fast tracking drugs. Orphan drugs. Preclinical trials. Toxicity testing. In Vivo toxicity testing. Metabolic stability testing. Clinical trials. Phase I. Phase II. Phase III. Phase IV.

Main literature

Graham L. Patrick     An Introduction to Medicinal Chemistry.

Robert M. Rydzewski    Real World Drug Discovery

C. Wermuth, D. Aldous, P. Raboisson, D. Rognan  The Practice of Medicinal Chemistry

J. Holenz   Lead Generation

Li Di and E. H. Kerns    Drug-Like Properties: Concepts, Structure Design, and Methods

Assessment strategy

Assessment criteria

Exam, presentation

The exam consist of two parts. The first part of examination is written exam followed by oral discusion. The second part of examination is a presentation. The presentation is based on a realtionship of the topic of doctoral studies and drug design process.

 Assessment criteria are related to the ability to operate with basic knowledge, the ability to apply it to solve various tasks, and the ability to reveal one's research topic in the context of the studied subject.

Virginija Dudutienė

dr

Approved by the Council of Graduate School of Life Sciences Center No 600000-…-… on the …. of …… 2021

Chairman