Drug Design Lecture (2023/2024) - PC 710 - SINAI UNIVERSITY

Pharm PharmDDProgram Program (2023/2024) (2023/2024) (PC 710) Lecture No. (2)...

Pharm PharmDDProgram Program (2023/2024) (2023/2024) (PC 710) Lecture No. (2) Design of Agonists and Antagonists By Dr. Abdelrahman Shalabi Lecturer of Medicinal Chemistry 12 October 2024 www.su.edu.eg 1  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Lecture’s Aim 1. Stereo-chemical aspects of drug-receptor interactions 2. Design of agonists and antagonists 12 October 2024 www.su.edu.eg 2  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Lecture’s Competencies 1. Utilize information from basic science to handle, identify, extract, design, prepare, analyze, and assure quality of synthetic/natural pharmaceutical raw materials and finished products 2. Integrate knowledge from fundamental pharmaceutical and medical sciences to explain the drug mechanism of action and assess the efficacy and safety in patient and community 3. Retrieve basic scientific drug information from different resources to solve problems related to human health and health systems. 4. Demonstrate the ability to perform pharmaceutical calculations, biostatistical analysis, bioinformatics, pharmacokinetics, and biopharmaceutics concepts and their applications in innovative drug delivery systems, dose adjustment bioequivalence research 12 October 2024 www.su.edu.eg 3  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Lecture’s Contents 1. Stereo-chemical aspects of drug-receptor interactions 2. Design of agonists and antagonists 12 October 2024 www.su.edu.eg 4  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Some definitions Structurally Nonspecific Drugs: The biologic effect of such drugs is correlated with physical properties, not with chemical structures. e.g. local anesthetics & hypnotics. Structurally specific Drugs: The biological action results essentially from chemical structure which should adapt itself to the 3-D structure of a receptor resulting in complex- formation. 12 October 2024 www.su.edu.eg 5  Pharm PharmDDProgram Program (2023/2024) (2023/2024) The activity of a given drug depends on a sequence of physicochemical events that begin when an active molecule penetrates a living organism. Three characteristic phases govern the biological activity of a drug in a living organism: The pharmaceutical phase: (Route of administration I.V. injection, oral, etc). The Pharmacokinetic phase: What the Body Does to a Drug? Pharmacodynamic phase: What a Drug Does to the Body?. 12 October 2024 www.su.edu.eg 6  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Stereo-chemical Aspects of Drugs A- Complementarity between drug and receptor. Receptors have a specific more or less rigid structure. Substances with similar activity contain common moieties arranged in space in analogous manner. The formation of a drug-receptor complex  is determined by steric factors  medicinal action will depend on the nature of this complex 12 October 2024 www.su.edu.eg 7  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Complementarity  specificity  activity Substitution of a bulky gp. by a small one, spatial reposition of gps. through inversion of an asymmetric center, …… can strongly alter the formation and stability of the drug receptor complex. In drug-receptor interaction, two values are of special importance: A) Electronic charge distribution in drug and receptor B) Conformations of drug and receptor. 12 October 2024 www.su.edu.eg 8  Pharm PharmDDProgram Program (2023/2024) (2023/2024) The activity of drugs depends on three structural factors: Stereochemistry of the molecule Distance between atoms or groups Electronic distribution and configuration 12 October 2024 www.su.edu.eg 9  Pharm PharmDDProgram Program (2023/2024) (2023/2024) A- Stereochemistry of drugs Compounds with the same molecular formula but different structures are called isomers 12 October 2024 www.su.edu.eg 10  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Stereochemistry and Biologic Activity R(-)-Epinephrine S(+)-Epinephrine 12 October 2024 www.su.edu.eg 11  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Trans Cis Diethylstilbestrol 12 October 2024 www.su.edu.eg 12  Pharm PharmDDProgram Program (2023/2024) (2023/2024) B- Interatomic distance Receptors possess, very regular spacing between peptide bonds Two distances are of great Interest: 1) The distance between two consecutive turns of the -helix= 5.38 Å. 2) The distance that separates the two peptide bonds when the protein is extended to maximum 3.61 Å. Usually known as the identity distance. 12 October 2024 www.su.edu.eg 13  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Identity distance Distance (-) 2 consecutive turns 12 October 2024 www.su.edu.eg 14  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Estradiol Trans Cis Diethylstilbestrol 12 October 2024 www.su.edu.eg 15  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Binding between a neurotransmitter (or drug) & a receptor. Ionic bonding Hydrogen bonding Van der Walls bonding 12 October 2024 www.su.edu.eg 16  Pharm PharmDDProgram Program (2023/2024) (2023/2024) The bonding forces must be large enough to change the shape of the receptor in the first place but not so strong that the messenger is unable to leave again. 12 October 2024 www.su.edu.eg 17  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 18  Pharm PharmDDProgram Program (2023/2024) (2023/2024) The design of agonist We know what binding groups are present in the receptor site and where they are, we can now design drug molecules to interact with the receptor considering the following requirements : 1) The drug must have the correct binding groups. 2)The drug must have these binding groups correctly positioned. 3)The drug must be in the right size for the binding site. 12 October 2024 www.su.edu.eg 19  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 20  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Possible agonists 12 October 2024 www.su.edu.eg 21  Pharm PharmDDProgram Program (2023/2024) (2023/2024) The structure in the following figure lack one or more of the required binding groups and might therefore be expected to have poor activity 12 October 2024 www.su.edu.eg 22  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 23  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 24  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 25  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Structure with a p-methyl group 12 October 2024 www.su.edu.eg 26  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Design of antagonists. 1) Antagonists acting at the binding site (competitive antagonism) 2) Antagonists acting outside the binding site (Non-competitive antagonism) Allosteric Antagonism by antagonist umbrella effect 12 October 2024 www.su.edu.eg 27  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 28  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 29  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 30  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 31  Pharm PharmDDProgram Program (2023/2024) (2023/2024) There are many antagonists which bear no apparent structural similarity to the native neurotransmitter and can not possibly fit the geometrical requirements of the binding site 12 October 2024 www.su.edu.eg 32  Pharm PharmDDProgram Program (2023/2024) (2023/2024) The antagonist may bind to a totally different part of the receptor. The process of binding could alter the shape of the receptor protein such as the neurotransmitter binding site is distorted 12 October 2024 www.su.edu.eg 33  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Allosteric antagonist 12 October 2024 www.su.edu.eg 34  Pharm PharmDDProgram Program (2023/2024) (2023/2024) - The receptor protein consists of amino acid residues, all of which are capable of interacting with a visiting molecule. So, there will almost be areas close to the binding site which are capable of binding through van der Waals, ionic, or hydrogen bonding forces. - These areas may not be used by natural neurotransmitter, but they can be used by other molecules. 12 October 2024 www.su.edu.eg 35  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Antagonism by umbrella effect 12 October 2024 www.su.edu.eg 36  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 37  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Partial agonist Compounds bind to the receptor site and block access to the natural neurotransmitter They also activate the receptor very weakly such that a slight signal is received Another explanation for partial agonism The molecule might be capable of binding to a receptor in two different ways by using different binding groups. One method of binding would activate the receptor, while the other would not 12 October 2024 www.su.edu.eg 38  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 39  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Lecture’s References Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th Ed.; Beale, J. M., Block, J. H., Eds.; Lippincott Williams & Wilkins: Philadelphia, 2011. Williams, D. A. Foye's Principles of Medicinal Chemistry. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2013 Patrick, G. An Introduction to Medicinal Chemistry. 6th ed. Oxford: Oxford University Press; 2017. 12 October 2024 www.su.edu.eg 40