Lecture 3: Drugs And Enzymes PDF

Lecture 3 Drugs and Enzymes Prof. Trader PharmSci 177/277 and Chem 177 Winter 2025 Classifications of Enzymes The Active Site Substrate Binding- Induced Fit Induced fit - Active site alters shape to maximize intermolecular bonding Induced Fit Favors Reactivity- LDH ...

Lecture 3 Drugs and Enzymes Prof. Trader PharmSci 177/277 and Chem 177 Winter 2025 Classifications of Enzymes The Active Site Substrate Binding- Induced Fit Induced fit - Active site alters shape to maximize intermolecular bonding Induced Fit Favors Reactivity- LDH Catalytic Mechanisms Acid/Base Nucleophilic Mechanisms Serine Cysteine Nucleophilic Mechanism Example Chymotrypsinà Catalytic Triade Chymotrypsin preferentially cleaves proteins at sites where the carboxyl side of the amide bond is an aromatic ring (F, Y, W). How can we use this information to design inhibitors?  Trap the Serine -The nucleophilic serine attacks the electron-deficient ketone to form a stabilized tetrahedral complex. O NH F O F F  Bind with the His -TPCK Inhibition O Cl O HN S O H H+ Allosteric Regulation of Enzymes Allosteric Regulation of Enzymes Cont.  Allosteric Enzyme Inhibitors Allosteric Inhibition is common when targeting kinases Kinases are proteins that covalently add a phosphate group to a target using ATP as the phosphate source. https://www.assaygenie.com/blog/protein-kinases  Kinase MOA DOI: 10.1074/jbc.270.38.22105  Kinase Allosteric Inhibitor MEKà Mitogen-activated protein kinase Regulates cell growth and survival Anti-cancer target Kinases need to bind ATP AND the substrate it will phosphorylate ATP is in the active site MEK1  Design of MEK1 Inhibitors The inhibitors are non-ATP competitive and bind to a unique pocket https://doi.org/10.1016/j.bmcl.2008.10.108 The inhibitors are non-ATP competitive and bind to a unique pocket More Target Binding Target Binding Cont. Target Binding Cont.  Which amino acids in my binding pocket form critical interactions with my drug? Determine using an alanine scan Retain potency but decrease selectivity? https://en.wikipedia.org/wiki/Alanine_scanning