36 Questions
Which term refers to chemical substances that interact with a biological system to produce a physiological effect?
Bioisosteres
What is the key principle of lead optimization in medicinal chemistry?
Optimizing target interaction
In drug-receptor interactions, what do bioisosteres mainly focus on?
Modifying functional groups while retaining biological activity
Which type of isosteres mimic the transition state of a reaction rather than the substrate or product?
Transition state isosteres
What is the primary goal of using isosterism and bioisosterism in medicinal chemistry?
To enhance the selectivity of drugs
Which text would be useful for referring to an overview presentation on relevant pages regarding medicinal chemistry?
'Medicinal Chemistry: An Introduction' by Thomas, G.
What factor affects the affinity of a drug to its receptor by influencing the stereochemical fit and shape complementarity?
Intermolecular interaction forces
Which term refers to the strength of binding of a single molecule to its ligand, typically measured by the equilibrium dissociation constant (KD)?
Affinity
What type of compounds produce a biological response by having affinity to their target but not activating the receptor?
Antagonists
Which chemical properties are involved in controlling the Drug-Receptor Interaction through non-covalent interactions?
Ion-dipole interactions and Charge-transfer complexes
Which term refers to the dissociation constant used to evaluate and rank the strengths of bimolecular interactions?
Equilibrium constant (Kd)
Why do optical isomers act differently in biological systems?
Because of their stereochemical fit with receptors
What type of interaction do anticholinesterase agents have with enzymes at the active site?
Covalent bonding
Which process does Parathion undergo to inhibit acetylcholinesterase irreversibly?
Phosphorylation
What is the active metabolite of Parathion that is used for the treatment of glaucoma?
Paraoxon
What is the key principle in lead optimization when optimizing target interactions?
Bioisosteres
In drug-receptor interaction, what is used to optimize access to the target in Prodrugs and drug optimization?
Transition state isosteres
Which type of agents interact non-selectively with all enzymes containing serine at the active site?
Acylating agents
Which type of bioisosterism involves the use of a double bond to position essential functional groups into a particular spatial arrangement?
Non-classical Bioisosterism
In classical bioisosterism, replacement of OH by an amino group leads to the formation of which antimetabolite?
Aminopterin
Which group is often used as a bioisostere for an amide in drug design?
Pyrrole ring
What type of isosteres are utilized to design transition state analogues for enzyme inhibitors?
Transition state (TS) isosteres
Which atom or group is commonly substituted by fluorine due to similar van der Waals radii and electronegativity?
-OH
What steric factor is considered less important when a sulfonamide group replaces a phenol hydroxy in catecholamines?
Acidity
Which type of covalent bonding leads to irreversible binding between a drug and a receptor?
Alkylation
In the context of bioisosteres, what does 'N C P + + As+' refer to?
Trivalent isosteres
What term describes the replacement of functional groups with other groups having similar properties?
Isosterism
What is the concept of isosterism applied to in drug design?
Functional groups
What law accounts for similarities in groups having the same number of valence electrons?
Grimm's Law
Which of the following is NOT considered a classical bioisostere according to the text?
Different electron distribution
What is a challenge mentioned in relation to relating physico-chemical properties to biological activity?
Difficulty in simultaneous interpretation
Which functional group can be ionized at physiological pH, imposing a positive charge on the molecule?
-NH2 (Amine)
In isosterism, what does the concept of ring equivalents refer to?
Exchangeable groups in aromatic ring systems
'Bioisosteres' are defined as groups with near equal shapes, volumes, and electron distribution that exhibit similar what?
'Biological activity'
'Chemical isosterism' was developed to describe similarities in physical properties based on what characteristic?
'Valence electrons'
What term describes replacing -CH=CH- in benzene with -S- or -O-?
Isosterism
Study Notes
Absorption, Distribution, Metabolism, Excretion (ADME)
• Pharmacokinetics and pharmacodynamics are crucial in drug development • Lead discovery and optimization involve structure-activity relationships, binding interactions, and pharmacophores
Functional Group Modification: Isosterism
• Isosteric replacement: replacing functional groups with similar physical and chemical properties • Coined by Langmuir (1919) to describe similarities in physical properties (e.g., atoms with the same number of valence electrons) • Grimm's Hydride Replacement Law (1925) accounts for similarities in groups having the same number of valence electrons
Bioisosteres
• Groups or molecules with similar physico-chemical properties (shape, volume, electron distribution) having similar biological activity • Difficult to relate physico-chemical properties to biological activity, as many properties are involved simultaneously • Classical bioisosteres obey original conditions of Langmuir and Grimm • Non-classical bioisosteres do not obey steric and electronic definitions of classical bioisosteres
The Drug-Receptor Interaction
• A drug is a chemical substance that interacts with a biological system to produce a physiological effect • Drug-receptor interaction involves physical and chemical characteristics of drugs (e.g., solubility, surface activity, partition coefficient) • Target or receptor: a cellular macromolecule that a drug binds to initiate its effects (e.g., protein, nucleic acid, lipid, carbohydrate)
Factors Controlling the Drug-Receptor Interaction
• Steric factors (stereochemical fit; complementarity of shape) • Non-covalent interactions (electrostatic effects, hydrogen bonding, hydrophobic interactions, van der Waals or London Dispersion forces) • ADME processes (pharmacodynamics and pharmacokinetics)
Covalent Bonding and the Drug-Receptor Interaction
• Formation of a covalent bond between a drug and a receptor leads to irreversible binding (irreversible inhibitor) • High reactivity can lead to high toxicity, used only for prolonged effects (bactericides, anticancer, pesticides)
Transition State Isosteres
• A special type of isostere used to design transition state analogues • These drugs are enzyme inhibitors, mimicking the crucial features of the transition state but stable to enzymatic reaction
Test your knowledge on Drug-receptor interactions and Isosteres from Lecture 2 of MSOP1016 - The Science of Medicine 3 at Medway School of Pharmacy. Topics include Isosteres/Bioisosteres, Chapter 13 sections 13.1.15 & 13.3.7, and Chapter 14 from the book 'An introduction to medicinal chemistry' by Graham Patrick.
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