Intro to Med Chem 1

Drug intermolecularforces intermolecularforces

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Unformatted text preview: binding sites/regions on target Intermolecular forces Most drugs are in equilibrium between being bound and unbound to their target Binding site Binding site Drug Drug Macromolecular target Unbound drug Macromolecular target Bound drug Intermolecular forces Intermolecular forces Electrostatic interactions Ion­dipole Dipole­dipole Hydrogen bonding van der Waals/dispersion forces Electrostatic interactions Electrostatic interactions Strongest of the intermolecular forces Not the same as ionic bonding Attraction vs. repulsion Strength is inversely proportional to the distance between the ions Stronger interactions occur in hydrophobic environments Electrostatic attractions are the most important initial interactions as a drug enters the binding site O Drug Drug NH3 O H3N Target O Target O Ion­dipole interactions Ion­dipole interactions Charge on one molecule interacts with the dipole of another Involved in solvation of ions in water Stronger than a dipole­dipole interaction O δ− R C δ+ R C O O Binding site O δ− R C δ+ R Binding site H3N Dipole­dipole interactions Occurs if the drug and the binding site have dipole moments Dipoles align as the drug enters the binding site Strength decreases with distance δ− O δ+ C R Dipole moment R Localized d ipole moment R O C R Binding site Binding site Hydrogen bonds Hydrogen bonds Strongest dipole­dipole interaction Occurs between an electron­deficient hydrogen and an electron­rich heteroatom The electron­deficient hydrogen is attached to a heteroatom (O or N) Hydrogen bond donor (HBD) The electron­rich heteroatom is O or N Hydrogen bond acceptor (HBA) δ- δ+ XH Drug δY Target H BD H BA δDrug Y H BA δ+ δHX Target H BD Hydrogen bonds Hydrogen bonds Vary in strength The interaction involves orbitals and is directional Optimum orientation X­H bond points directly to the lone pair on Y Angle between X, H and Y is 180° X Y H Hybridized 1s orbital orbital HBD Hybridized orbital HBA X H Y van der Waals interactions van der Waals interactions Weakest IF Occur between hydrophobic regions Transient areas of high and low electron densities Often hydrophobic pockets on the surface of target Temporary dipoles The overall contribution of van der Waals interactions can be crucial to binding Hydrophobic regions δ+ δ- Transient dipole on drug DRUG δ+ δ- δ- δ+ van der Waals interaction Binding site Desolvation penalties Polar regions of a drug and its target are solvated prior to interaction Desolvation is necessary and requires energy The energy gained by drug­target interactions must be greater than the energy required for desolvation H O H H O H H O O C R R O H C R H O H R O H H C H Binding site O O R R Binding site Binding site Desolvation: Energy penalty Binding: Energy gain O Desolvation: hydrophobic interactions Hydrophobic regions of a drug and its target are not solvated Water molecules interact with each other and form an ordered layer next to hydrophobic regions Negative entropy Hydrophobic interactions between a drug and its target “free up” the ordered water molecules Increase in entropy Beneficial to binding DRUG Drug Binding DRUG Drug Binding site Structured water layer Structured around hydrophobic regions around Binding site Unstructured water Unstructured Increase in entropy Hydrophobic regions regions Water Where do drugs interact? Where do drugs interact? 1. 2. 3. 4. Four main targets: Lipids Carbohydrates Nucleic acids Proteins Structure I. Lipids I. Lipids Polar head (hydrophilic) Nonpolar tail (hydrophobic) Where are lipids typically located? Cell membranes of most interest...
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This document was uploaded on 03/13/2014 for the course CHEM 4201 at Clayton.

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