BO4203 Conventional and Rational Drug Discovery Strategies Syllabus:

BO4203 Conventional and Rational Drug Discovery Strategies Syllabus – Anna University PG Syllabus Regulation 2021

OBJECTIVES

The course aims to,
 Expose the students to various principles and methodologies involved in the drug discovery and validation process.
 Provide an insight about in-silico based drug discovery techniques.
 Explain the various stages of drugdiscovery.
 Appreciate the importance of the role of genomics, proteomics and bioinformatics in drug discovery
 Explain various targets for drugdiscovery.
 Explain various lead seeking method and lead optimization
 Appreciate the importance of the role of computer aided drug design in drug discovery

UNIT I DRUG DESIGN STRATEGIES

Various approaches in drug discovery process– conventional versus rational, drug targets, lead identification; Principles of ligand chemistry– lead optimization, pharmacophores, bioisosteres, principles of ligand chemistry such as configuration, conformation, chirality, isosteric replacement; Parameters of ligand design such as–Phytochemical, geometric, conformational, topological, partitional, steric, stereochemical and electronic properties of drug molecules; Pharmacokinetic parameters of ligand design such as- Lipinski “rule of 5”, partition coefficient, Hammet constant, Hansch analysis. Biological, chemical and physical descriptors used in QSAR and QSPR. Statistical methods used for analysing QSAR/ QSPR data

UNIT II IN-SILICO METHODS FOR DRUG DISCOVERY

Introduction to molecular docking, Principles of macromolecule-ligand docking, docking algorithms, AUTODOCK; de novopharmacophore elucidation/ drug design for structurally well-defined receptor targets from case studies (Eg. HIV protease inhibition, ACE inhibition); Molecular dynamic simulations, relative energy, energy minimization methods, ligand binding free energy calculations (both simulation and empirical methods), intermolecular interactions, forces related to drug binding, force-field calculations including solution, role of solubility in drug binding and pKa, Poisson Boltzmann Surface Area (PBSA), AMBER,GROMOS and GROMACS.

UNIT III COMBINATORIAL CHEMISTRY FOR DRUG DISCOVERY

Combinatorial Chemistry in drug development, Biopolymers as natural libraries, Selection and evolution of expression genetic libraries, Combinatorial assembly of antibody genes, Molecular solutions to Combinatorial problems, Solid-Phase peptide synthesis, Peptide on pins, Other iterative deconvolution strategies, Examples of Split/Couple/Mix Peptide Libraries, Positional Scanning., Polystyrenes, Grafted supports, Coupling strategies, linkers, Supported Solution and Phase Synthesis, analytical methods for solid-phase.

UNIT IV HIGH THROUGHPUT SCREENING IN DRUG DISCOVERY

Classification of HTS: Protein based biochemical screens, methods of analytical biochemistry used in HTS (photometry, purification, electrophoresis, kinetic assay, radioisotopes, immunoassay, HTS FACS based assays). Assay design for HTS and statistical treatment of the results for decision. Introduction to state of the art technologies used in HTS (including automated liquid handling machines (robots), Microfluidic Tools for HTS, Miniaturization); preclinical toxicological studies, Correlation between in-vitro and in-vivo screens.

UNIT V GENETIC BASED TOOLS IN DRUG DISCOVERY PROCESS

Basics of gene silencing, transgenic worms in drug screening; designing SiRNAs, Types of RNAi Screens– Loss of Function screens (LOF), Synthetic Lethal screen, Mini-clonogenic RNAi screen; optimizing, and implementing high-throughput siRNA genomic screening for the discovery of survival genes and novel drug targets, siRNA HTS Screening for identification of targeted pathways in biological systems. Microarray technologies- Classification with microarrays and class prediction, Visualization and functional analysis. Bio molecular pathways, gene ontology, genome browsing, Gene expression biology, microarray platforms (Eg. Affymetrix); Preprocessing of microarray data for Image analysis, quality control and array normalization.

TOTAL :45 PERIODS

COURSE OUTCOMES:

At the end of the course the student will be able to,
CO1 learn about different conventional and rational drug discovery strategies.
CO2 know about molecular modelling in drug development.
CO3 understand the Gene based tools and high throughput screening methods.

REFERENCES

1. Williams, D.A. and Lemke, T.L., “Foye’s Principles for Medicinal Chemistry” 5th Edition, Lippincott, Williams & Wilkins, 2002.
2. Leach, AR, “Molecular Modeling& Drug Design”, 2nd Edition, John Willy, 2000.
3. GROMOS and GROMACS Manuals.
4. Murray, K.J. “Principles and Practice of High Throughput Screening”. Blackwell Scientific Publishers, 2004.
5. Ye, S., and Day, I.N.M. “Microarrays and Microplates: Applications in Biomedical Sciences”. BIOS 2003.
6. “Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry”.12th Edition, Lippincott-Raven Publisher, 2010.
7. Fassina, G. “Combinatorial Chemistry and Technologies: Methods and Applications”, 2nd Edition, CRC Press, 2005
8. Janzen W. P. “High Throughput Screening: Methods and protocols”. Humana Press. 2002