Drug-Receptor Interactions PDF

Pharmaceutical Chemistry Department The Enthalpic Component of Binding: Drug-Receptor Interactions Section (3) Molecular Recognition Laboratory session 3  Molecular Recognition 1) electrostatic 2) Hydrogen 3) Hydrophobic complementarity bo...

Pharmaceutical Chemistry Department The Enthalpic Component of Binding: Drug-Receptor Interactions Section (3) Molecular Recognition Laboratory session 3  Molecular Recognition 1) electrostatic 2) Hydrogen 3) Hydrophobic complementarity bonding interactions Drug Selectivity Drug affinity Laboratory session 3  Drug affinity and Gibbs free energy ΔG = ΔH – TΔS Enthalpy Entropy Drug-Receptor Interactions Rigidification (Conformational restriction) Interactions that contribute to binding Laboratory session 3  Interactions Electrostatic Hydrophobic (Steric) Ionic Interactions Charge-Dipole and Dipole-Dipole For each Interaction: Hydrogen Bonds 1- Definition 2- Factors affecting its E Halogen Bonds 3- Impact on binding π-π interactions Cation-π Laboratory session 3 interactions (1) Electrostatic Interactions: 𝒒𝒊. 𝒒𝒋 𝑬= 𝜺. 𝒓𝒊𝒋 𝒒𝒊 𝒓𝒊𝒋 𝒒𝒋 Laboratory session 3  (1) Electrostatic Interactions: 1.1 Ionic Interactions (Charge-charge) Interaction: 1- Definition 2- Factors 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.1 Ionic Interactions (Charge-charge) Factors affecting the strength of Ionic interactions: 𝒒𝒊. 𝒒𝒋 1- Distance 𝑬= Long-range interaction 𝜺. 𝒓𝒊𝒋 2- Dielectric Constant (ε) Water vs Protein 𝒒𝒊 𝒓𝒊𝒋 Interaction: 𝒒𝒋 1- Definition 2- Factors Laboratory session 3 3- Impact  (1) Electrostatic Interactions: 1.1 Ionic Interactions (Charge-charge) dominates the initial long-range interactions Interaction: 1- Definition Drug Selectivity 2- Factors 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.2 Charge-Dipole & Dipole-Dipole Interactions atoms of different electronegativities → asymmetric distribution of electrons → electronic dipoles Interaction: 1- Definition 2- Factors 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.2 Charge-Dipole & Dipole-Dipole Interactions Factors affecting the strength of the interactions: 𝒒𝒊. 𝒒𝒋 1- Charge 𝑬= Less than ionic 𝜺. 𝒓𝒊𝒋 2- the orientation of the dipole moments attractive or repulsive Interaction: 1- Definition 2- Factors Laboratory session 3 3- Impact  (1) Electrostatic Interactions: 1.2 Charge-Dipole & Dipole-Dipole Interactions Any molecule → electronegativity differences bet. atoms → dipole moments → key contributors to the overall strengths of drug-receptor interactions Interaction: 1- Definition 2- Factors 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.3 Hydrogen Bond Interaction: 1- Definition 2- Factors 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.3 Hydrogen Bond Factors affecting the strength of the interactions: 𝒒𝒊. 𝒒𝒋 1- Distance and Angle 𝑬= 2.5 - 3.2 A˚ 𝜺. 𝒓𝒊𝒋 130-180°:optimal 3 atoms aligned 2- Dielectric Constant (ε) buried HB more important than in solvent-exposed regions Interaction: 1- Definition 2- Factors Laboratory session 3 3- Impact  Hydrophobic pocket in HER2 kinase binding site IC50= 1.6 nM IC50= 2.1 nM IC50= 2.1 nM IC50= 6 nM  (1) Electrostatic Interactions: 1.3 Hydrogen Bond 1) Drug Selectivity directionally specific interactions 2) Binding affinities increase by one order of Interaction: magnitude per HB 1- Definition 2- Factors 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.3 Hydrogen Bond → NB: The number of hydrogen bonds in a drug molecule may be limited by requirements on polarity for absorption and permeation. → Lipinski's rule of five … No more than 5 hydrogen bond donors … No more than 10 hydrogen bond acceptors Interaction: 1- Definition 2- Factors 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.4 Halogen Bond (XB) Interaction: Lewis base (has an available pair of electrons) 1- Definition 2- Factors 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.4 Halogen Bond (XB) Factors affecting the strength of the interactions: 𝒒𝒊. 𝒒𝒋 1- Distance 𝑬= 𝜺. 𝒓𝒊𝒋 2- Angle 180°: 3 atoms aligned Interaction: 1- Definition 2- Factors Laboratory session 3 3- Impact  (1) Electrostatic Interactions: 1.4 Halogen Bond (XB) The strength of XB allows it to compete with HB Interaction: 1- Definition 2- Factors 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.5 Cation-π Interactions Interaction: 1- Definition 2- Factors 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.5 Cation-π Interactions Interaction: 1- Definition 2- Factors 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.5 Cation-π Interactions Interaction: 1- Definition Process by which acetylcholine is recognized 2- Factors and bound to the muscarinic receptor 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.5 Cation-π Interactions Interaction: 1- Definition Process by which acetylcholine is recognized 2- Factors and bound to the muscarinic receptor 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.6 π-π interactions Interaction: 1- Definition 2- Factors 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.6 π-π interactions Interaction: 1- Definition 2- Factors 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.6 π-π interactions Interaction: 1- Definition 2- Factors 3- Impact Laboratory session 3  (1) Electrostatic Interactions: 1.6 π-π interactions Factors affecting the strength of the interactions: 1- Orientation 2- Electronic properties of the π- system a) T-shaped structure : electron-withdrawing substituent → interacting H more positive Interaction: & electron-donating substituent 1- Definition → increase π-electron density 2- Factors Laboratory session 3 3- Impact  (1) Electrostatic Interactions: 1.6 π-π interactions Factors affecting the strength of the interactions: 2- Electronic properties of the π- system b) parallel alignment : 2 aromatic partners: (1) bearing strong electron-donor (2) and the other strong electron- acceptor groups Interaction: → parallel stacking complexes 1- Definition 2- Factors Laboratory session 3 3- Impact  Tyr → OH → EDG Factor Xa inhibitors (δ-) C=O → EWG (δ+) (2) Hydrophobic Interactions (Steric Interactions) Drug affinity Laboratory session 3  (2) Hydrophobic Interactions (Steric Interactions) Van der Waals or London dispersion forces the universal forces responsible for attractive interactions between nonpolar molecules Interaction: 1- Definition 2- Factors 3- Impact Laboratory session 3  (2) Hydrophobic Interactions (Steric Interactions) Factors affecting the strength of the interactions: 1- Distance short-range interactions 2- Steric Match (shape complementarity) individual interactions between pairs of atoms are relatively weak (about 2 kJ/mol), the total contribution to binding from Interaction: dispersion forces can be very significant if 1- Definition there is a close fit between drug and 2- Factors receptor (good entropy) Laboratory session 3 3- Impact  (2) Hydrophobic Interactions (Steric Interactions) Drug affinity “Hydrophobic Effect” Interaction: 1- Definition 2- Factors 3- Impact Laboratory session 3 Inhibition of estrogen biosynthesis by the third generation aromatase inhibitors (AIs) exemestane (EXM), the frontline therapy for postmenopausal estrogen-dependent breast cancer EXM: IC50= 50 nM  ⇧ hydrophobic interactions → 5-fold increase in activity (high impact of hydrophobic interactions in a hydrophobic binding site) IC50= 11 nM  Miscellaneous Interactions: 1. Metal chelation biological targets → catalytic metal in the binding sites (mostly Zinc) Chelation: -ve ions or atoms carrying lone pairs bind to metal via one or more coordinate bonds. Ex: SH, SO3H, SO2NH2, COOH, CONHOH (hydroxamic acid group). Laboratory session 3  Miscellaneous Interactions: 2. Covalent bond Irreversible binding to the target Permanent loss of its function **Examples: Anti-bacterials (penicillin) Anti-viral drugs Insecticides Laboratory session 3 Questions 1- This is the muscarinic receptor binding site, predict the types of interactions needed to be fulfilled by the ligand to achieve good receptor-ligand binding. Laboratory session 3  2- Based on your study of the muscarinic receptor binding site, which of the following ligands offers the best physicochemical complementarity ? (a) (b) (c) Laboratory session 3  Assignment Summarize the different types of drug-receptor interactions that you studied in a tabular form or in any given diagram (e.g. mind map … etc.) that you find more suitable, highlighting the key differences between these interactions, the impact of their contribution to the binding process, the factors affecting each of them and an example to that type of interaction. Be creative! Laboratory session 3