FFKKM0371 - Medicinal and Biostructural Chemistry

The course objective is to give students insight into the molecular mechanisms of action of selected drugs and to acquaint them with the fundamental principles of drug design and discovery. The course aims to expand students’ knowledge of the chemical and structural factors relating to the main drug groups and to give examples of the use of chemical principles to clarify the interaction of drugs with macromolecules in the organism. This includes a basal understanding of the 3-D structure of drugs and target macromolecules. Students shall be able to use the vast number of biostructural information on relevant target macromolecules available on internet databases, and to use such information about proteins primary sequences and 3-D structures of macromolecules in the context of drug design.

Course teaching is based on the assumption that students have previous knowledge from basal courses in organic chemistry, physical chemistry, biochemistry and general pharmacology, preferably corresponding to the content of the compulsory courses on these topics in the BSc in Pharmacy programme. Special IT knowledge is not a requirement, but all students need to bring a laptop computer for the computer exercises.

The course will deal with the most important principles of drug design and discovery, bioinformatics and structural biology. Genome structure will be introduced focusing primarily on the importance of systematic variations of the human genome in relation to diseases. Sequence alignment will be discussed and students will get to use internet based tools for sequence analyses. The course will give basis knowledge about the structure of proteins, including 3-D structural information and experimental methods for structure determination. Methods for design and development of substances with specific or selective effect on biochemical or physiological processes will be introduced. Emphasis will be on the significance of steric, stereochemical, conformational and electrostatic factors for drug design. The importance of changes of structural and physico-chemical parameters in order to obtain drugs with appropriate pharmacokinetic properties will be discussed. The importance of the prodrug principle for improving the pharmacokinetic properties of drugs will also be addressed. Students will be introduced to systems biology and the importance of protein-protein interactions. Certain aspects of chemotherapeutic and antiviral substances will be covered, with emphasis on the chemical and structural factors crucial to the activity of these substances. Enzyme structure and the concept of enzyme inhibitors will also be dealt with and discussed in relation to developing drugs with anti-carcinogenic or anti-viral effects. Ion channels as the pharmacological and therapeutic point of intervention and compounds with direct impact on specific ion channels will be introduced. The course will place considerable emphasis on the study of structure-activity relationships in certain groups of drugs. Some groups of psychotropic drugs, hypnotics and immunomodulating agents will be studied. In general, course teaching will concentrate on the structural factors relative to the effect of certain drugs. Central neurotransmitter systems and research in drug design on these systems will be mentioned. The pharmacokinetic aspects related to the passage of the blood-brain barrier will be highlighted. Course teaching will relate primarily to the organo-chemical aspects of drug activity and development, but will also cover bio-inorganic chemistry topics. These last topics will focus on the role of metal ions in biochemical processes and their importance for the biological effect of certain metal-binding substances. Students will study the selective removal of toxic metal ions from the organism by the forming of chelates with various organic compounds.

• To be able to account for the relationship between chemical structure and biological activity of important drug classes
• To be able to account for the key principles applied when designing and developing new drugs on a rational basis
• To be able to account for the key chemical, physico-chemical and pharmacokinetic properties of the main drug groups
• To be able to use basic tools for 3D-viewing and the information available from sequenced genomes to solve problems related to drug design and development
• To be able to use basic knowledge about conformation of small molecules, stereochemistry, pKa-values, ionization and electrostatic ligand-macromolecule interactions in the discussion in the mechanisms of action of drugs at the molecular level.

Kristian Strømgaard (lectures), Department of Medicinal Chemistry

Michael Gajhede (class lessons and computer exercises), Department of Medicinal Chemistry