| CODE | PHR3250 | ||||||||||||
| TITLE | Medicinal Chemistry 2 | ||||||||||||
| UM LEVEL | 03 - Years 2, 3, 4 in Modular Undergraduate Course | ||||||||||||
| MQF LEVEL | 6 | ||||||||||||
| ECTS CREDITS | 4 | ||||||||||||
| DEPARTMENT | Pharmacy | ||||||||||||
| DESCRIPTION | Bioisosterism - History of the Concept of Bioisosterism - Langmuir (1919): Comolecules and Isosteres, Grimm (1925), Erlenmeyer (1932), Friedman (1951): Concept of Bioisosteres, Thornber (1979), Burger (1991), Cheminformatics Era (1993). - Classification of Typical Isosteres; Monovalent Atoms or Groups; Divalent Isosteres; Trivalent Atoms or Groups; Tetrasubstituted Atoms; Ring Equivalents; A Simple Concept for Many Applications; Adapt Chemical Structures to Feasible Syntheses; Change the Type of Biological Activity. - Examples: Tricyclic Structures, Angiotensin-II Receptor Ligands, Steroid Analogs, Achieve Patentability, Mimic an Endogenous Ligand, Improve Potency, Improve Selectivity, Reduce Side Effects, Reduce Toxicity, Improve Bioavailability, Exploit Metabolism, Modify pKa, Increase Chemical Stability, Combinatorial Chemistry. - Examples of Natural Bioisosteres: Amino acids, Nucleotides, Sugars, Lipids, Steroid Hormones, Carbohydrates, Catecholamines, Penicillins and Cephalosporins. - Dictionary of Bioisosteres: Allyl, Amide, Amino-Acids, Azomethine, Benzene, Carbonyl, Carboxylic Acid, Catechol, Ester, Halogen, Hydrogen, Hydroxyl, Indole, Isopropyl, Naphthalene, Peptide Surrogates, Phenol, Pyridine, Ring, Sulfonyl, Spacer, Thioether, Thiourea. - Examples of Bioisosteric Transformations- Four Types of Bioisosteric Transformations: Ring-to-Ring Transformations, Chain-to-Ring Transformations, Ring-to-Chain Transformations, Chain-to-Chain Transformations with examples of each case. - Commercial Bioisosteric Drugs: Angiotensin Receptor Blockers (ARBs), COX-2 Inhibitors, Anti-Inflammatory NSAIDs, Antiarrhytmic Beta-Adrenergics, Neuroleptics, Anti-Ulcers, Male Erectile Dysfunction Drugs, Benzodiazepines, Antibacterial Sulfonamides, Beta-Lactam Antibiotics, Local Anesthetics, Glucocorticoid Steroids, Statin Drugs. - Patent Issues with Bioisosterism- Limits of Patent Infringements on Structures?- The Viagra-Levitra Case; The Diazepam-Clobazam Example; Patent Issues with Chiral Enantiomers; Patentable Drugs by Bioisosterism; Programs and Databases on Bioisosterism. - Limitations and the Future- The Receptor is the Ultimate Decider; The Multidimensional Nature of Bioisosterism; Shape; Lipophilicity; Electronic Distribution; Hydrogen-Bond Capacity; Can Bioisosterism be Quantified?; The Cheminformatics Era; Docking can be used to Generate Bioisosteres; Strategic and Financial Considerations. - Examples of Success and Failures. Introduction to Protein-Ligand Binding - Receptor-Based Drug Design- Macromolecular Targets; Mechanism of Action of Drugs; Drug Targets; Contribution of Recombinant Technologies ; Operational Strategy: Docking. - Analytical Process: Data Collection: X-Ray Crystallography; NMR Spectroscopy; Homology Models. - Principles of Analysis: Analysis of the Morphology of the Active Site; Morphology of the Active Site of a Protein Kinase; Complexes with Ligands; Forces That Contribute to the Binding; The Molecular Recognition Process; Electrostatics; Hydrogen Bonding; Protein Capabilities in Hydrogen Bonding; Elementary Hydrogen Bond Interactions; Example of the Hydrogen Bond Binding; Hydrophobic Interactions; Example of Hydrophobic Binding; Strengthening Hydrophobic Interactions; Hydrogen Bond Features; Elementary Electrostatic Interactions; Strength of Electrostatic Interactions; Example of Electrostatic Interactions; Increase of Potency by the Formation of a Salt Bridge; OH Analog Much Less Potent. - Example of Tight Interactions: An Example of a Tight Ligand-Receptor Interaction; The X-ray Structure of the Biotin/Streptavidin; The Binding Mode of Biotin with Streptavidin. - Receptor & Ligand Flexibility; Flexibility of the Receptor; Flexibility of The Ligand; Entropic Effects; Role of the Solvent; Solvation and Desolvation; Relay with Water Molecules; Relay with Several Water Molecules; Relay with Water Molecule Having Four H- Bonds; Prediction of Binding Modes; Binding Modes Predicted by Analogy; Inversion of Binding Modes; Inverted Binding Mode of Olomoucine; X-Ray Structure of ATP Bound to a Protein Kinase; Intuitive 2D Alignment for Olomoucine; Experimental Binding Mode of Olomoucine; Origin of the Inverted Binding Mode of Olomoucine; Inverted Binding Mode of Methotrexate; Intuitive 2D Alignment for Methotrexate; Experimental Binding Mode of Methotrexate ; Origin of the Inverted Binding Mode of MethotrexateBinding Mode Predicted from SAR. - Methods for Analyzing Binding- Analyzing Ligand-Receptor Binding; Ligand-Binding Predictions; Visual Analyses; Docking Analyses; Manual Docking with Computer Graphics; Automated Methods for Docking; Calculation of Binding Energies; Free Energy Perturbation Techniques; Energies from Force Field Calculations; Correlation with Biological Activities; Energies from Scoring Functions; Limitations of Scoring Functions; Calculating Desolvation Energies. - The Medicinal Chemistry (including the Structure 鈥� Activity relationships (SAR) of: - Tricyclic and related psychotherapeutic drugs; atypical antipsychotics; pro-drug approach to depot antipsychotics. - Monoamine Oxidase Inhibitors (MAOIs) and reversible MAOIs; Selective Serotonin reuptake inhibitors (SSRIs) and other antidepressants. - Benzodiazepines and the first benzodiazepine competitive antagonist. Buspirone, zolpidem. - Antibacterial drugs including tetracyclines, aminoglycosides, macrolides, sulphonamides, quinolones. - Drugs acting on the cardiovascular system. - Drugs acting on the endocrine system. - Steroids including cutaneous applications. Study-unit Aims: - To understand the importance of bioisoterism in contemporary drug design strategies. - To understand the financial implications of chiral switch drugs. - To understand the principles of protein:ligand binding at a molecular level. - To introduce further principles applied to drug design in various drug classes. Learning Outcomes: 1. Knowledge & Understanding: By the end of this study-unit, the student will be able to: - understand the concept of bioisosterism and its role in drug design. - appreciate the relationship between bioisosteres & adverse effect profiles. - appreciate the relationship between bioisosterism & patent issues. - understand that protein:ligand binding profiles are a function of inter-atomic interactions. 2. Skills: By the end of this study-unit, the student will be able to: - correlate the notion of bioisosterism with pharmacological activity and with the financial feasibility of contemporary drug design. - make accurate predictions regarding ligand binding modalities with their protein target based on mutual molecular interactions. Main Text/s and any supplementary readings: Lemke TL. Review of organic Functional Groups: Introduction to Medicinal Organic Chemistry. USA:Williams & Wilkins. 1992. ISBN 0-7817-4381-8. Foye WO. Principles of Medicinal Chemistry. USA: Lippincott, Williams & Wilkins 2008, ISBN 978-0-7817-6870-5. Smith HJ and Williams H. Eds. Introduction to the Principles of Drug Design, UK: Harwood Academic Publishers. 2005. ISBN 90-5702-037-8. Adrien Albert. Selective Toxicity: The Physico-Chemical Basis of Therapy. USA: Springer. 1985. ISBN 9870-4122-6020-9. Souidijn W. The Role of Medicinal Chemistry in Drug Research, Pharmaceutische Weekblad, Scientific Edition 1991; 13(4): 161-6. Burger鈥檚 Medicinal Chemistry & Drug Discovery. USA: John Wiley and Sons, ISBN 9780-4712-6694-5. |
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| RULES/CONDITIONS | Before TAKING THIS UNIT YOU MUST TAKE PHR2026 AND TAKE PHR2220 | ||||||||||||
| STUDY-UNIT TYPE | Lecture and Seminar | ||||||||||||
| METHOD OF ASSESSMENT |
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| LECTURER/S | Nicolette Sammut Bartolo Claire Shoemake |
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The availability of optional units may be subject to timetabling constraints. Units not attracting a sufficient number of registrations may be withdrawn without notice. It should be noted that all the information in the description above applies to study-units available during the academic year 2025/6. It may be subject to change in subsequent years. |
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