MOLECULAR MODELLING LABORATORY

Synopsis: This course will present drug development “Hit to lead selection and validation” as a process involving target selection, lead discovery and optimization using computer based method. Along the way the student will learn about molecular recognition and computer aided drug design as applied to the development of new drugs.

Course contents and teaching

Principal aims

To introduce students to molecular modelling techniques as applied to biological systems with particular emphasis on the methods used and their underlying theory. The student should gain a basic understanding of the available computational methods and their theoretical foundations; what time scales and length scales are accessible; what properties can be computed and to what level of accuracy; and what methods are most appropriate for different molecular systems and properties.

Relevant in silico tools along with success stories, possibilities and difficulties.will be also briefly presented.

Subject knowledge and understanding

Have an understanding of the theoretical background and application of computer modelling in medicinal chemistry; Understand the origins of intermolecular interactions, how to model them, and how to relate them to experimental data; Appreciate the advantages and disadvantages (critical ability) of different modelling methodologies .

Principal Learning Outcomes

a) Ability to implement the above methodologies in practice; b) Ability to analyse a given problem and select a suitable computational method for studying it; (c) Cognitive Skills: The key challenge for this module is for students to be able to design a molecular modelling experiment, and implement it efficiently on a computer. They will also further understand the statistical analysis and interpretation of the results and the relationship to laboratory experiments.(d) Subject-Specific/Professional Skills: Able to undertake molecular modelling to solve specified problems and critically evaluate data and articles.

Frontal Lessons.

According to "Regolamento Didattico di Ateneo (R.D.A.) i.e. University Didactic Regulations attendance of lessons is mandatory.

Should teaching be carried out in mixed mode or remotely, it may be necessary to introduce changes with respect to previous statements, in line with the programme planned and outlined in the syllabus.

Learning assessment may also be carried out on line, should the conditions require it.

Specific Contents

• Process of action of drugs. Pharmacodynamics: molecular targets: interactions between bio-active molecules and drug targets. Pharmacokinetics: adsorption, distribution, metabolism, elimination.

• Introduction to basic principles of protein-ligand interactions and a number of concepts in modern drug discovery.

• Rational drug design and introduction to computational methods.

• Conformational analysis: Geometry optimization and Energy Minimization methods. Quantum- and Molecular-mechanics methods (Force Field).

• Commercial(Cambridge Structural Database: CSD) and non-profit (Protein Brookaven Databank: PDB) crystallographic databases.

• Structure based methods, binding site analysis, dock¬ing, scoring functions and virtual screening.

• Application of docking techniques to the prediction of drug-target interactions.

• MIF methods : GRID, CoMFA.

• Ligand based design approaches including “traditional” (2D) QSAR (QSPR), 3D-QSAR (CoMFA, HASL) , Pharmacophore modelling.

• Introduction to chemioinformatics and Drug Development.

• Chemical and Drug Databases.

• Property calculations and property filtering.

• Molecular Similarity.

• Prediction of ADME (Administration-Distribution-Metabolism-Excretion) and toxicity of Drug molecule.

• Structural Bioinformatics in Drug Development (Protein Homology modeling).

• Molecular Dynamics.

TEXTBOOKS AND OTHER RESOURCES

Due to the cutting edge nature of this course and the rapid advances made in the field , a single primary text which adequately covers the content of this course has not been identified. Therefore each lecturer will provide the student with additional resources to supplement their lecture material. These resources will take the form of text books, journal articles (if available links to the electronic form of these resources will be provided) or web based resources.

Class Notes; Chemometry booklet; useful readings suggested from the teacher.