Exam 1: Properties of Drug: Target Interactions Condensed Notes PDF

LA 9.18.2022 EXAM 1: PROPERTIES OF DRUG: TARGET INTERACTIONS CONDENSED NOTES FOR MORE INFORMATION, REVIEW DR. HARRAHIL’S LECTURE SLIDES Describe the relationship between The law of mass action says that if Kon is high, there will be more binding and the law of mass b...

LA 9.18.2022 EXAM 1: PROPERTIES OF DRUG: TARGET INTERACTIONS CONDENSED NOTES FOR MORE INFORMATION, REVIEW DR. HARRAHIL’S LECTURE SLIDES Describe the relationship between The law of mass action says that if Kon is high, there will be more binding and the law of mass binding events. action - # Of binding events= [receptor]*[ligand]*kon - # Of dissociation events = [receptor: ligand] koff - At equilibrium, the number of binding events is equal to the number of dissociation events - What is Kd Describes how much drug we would expect to be bound and how much unbound. Most drugs are in the low nm range. Kd is usually given in units of M, mM, and nM. Kd is small when the concentration of receptor: ligand increases. A better drug has a smaller Kd, because there is more interaction between the drug (ligand) and its receptor and there is more stability. When Kd is small, the dissociation event is unfavorable. This is a good thing if we want our drug to bind well and tend not to dissociate. The [receptor:ligand] comples increases as Kd becomes smaller, and decreases as Kd becomes larger Thermodynamics of binding ∆𝐺° = ∆𝐻° − 𝑇∆𝑆° equation (Gibbs free energy) Describe ∆𝐻 The enthalpy of binding. - Remember that (-) delta H Inside of the cell, free flowing proteins are surrounded by water is favorable. So is (-) delta molecules. ∆H is determined by the energy required to break the G. bonds of the warer associations and then form interactions with our drug. A (-)∆H is achieved by increasing the energy of formation, Eform and thus we will be able to have a negative delta G. Remember that a (-) delta G is favorable, because it means that the reaction will be spontaneous. What equation links kinetics to thermodynamics? Is there electron sharing in No. There is no electron sharing in noncovalent interactions. noncovalent interactions? Noncovalent interactions are responsible for most binding affinity seen between ligands and targets. Noncovalent Interactions are exothermic, and they stabilize the receptor: ligand complex Note that different functional groups form different types of non-covalent interactions Which of the intermolecular bonds Electrostatic, i.e, ionic bonds. is the strongest? - These take place between groups of opposite charge. - The strength of an ionic interaction is inversely proportional to the distance between two charged groups. - Remember that electrostatic interactions are stronger in hydrophobic environments. At what pH would you expect *we need the acid to be (-) charged and the base to be Warfarin to interact most strongly positively charged in order for this ionic interaction to occur. with lysine? - the answer is 7. This is because at a pH of 7, our Warfarin (which has a pKa of 4.9 and is acidic), would be (-) charged an in the ionized form. At the pH of 7 our lysine would be (+) charged because it would be protonated. Hydrogen bonding: These bonds are between hydrogen and a (N or O atom). Fluorine is a weak hydrogen bond acceptor. The electron- rich heteroatom is called the hydrogen bond acceptor. The electron-deficient hydrogen is called the hydrogen bond donor. The best hydrogen bond donors are positively charged. The best hydrogen bond acceptors are negatively charged. - The carboxylate ion and the phosphate ion are great hydrogen bond acceptors Van der Waals interactions These are caused by temporary dipoles and occur between - Their overall contribution hydrophobic regions of drug and target. can be crucial to binding! Interactions drop off rapidly with distance Drug must be close to binding region for interactions to occur Transient areas of high and low electron densities cause temporary dipoles π-π stacking interactions These are a special case of van der wall interactions, and they occur when 2 aromatic systems are co planar Can be sandwiched, stacked, or t shaped. 2  - All of the electron density is above or below the plane. - These interactions are seen between aromatics in DNA and protein sidechains with aromatic rings in drug molecules Dipole-dipole interactions Can occur if drug and binding site have dipole moments -Rule of thumb: a bond with a difference of electronegativity that is greater than 0.5 will have a permanent dipole moment - Dipoles align with each other as drug enters binding site - Dipole alignment orientates molecule in binding site - the strength of interaction decreases with distance more quickly than with electrostatic interactions, but less quickly than with van der Waals interaction - example: Ketones and aldehydes Ion-dipole interactions - charge on one molecule interacts with dipole moment of another *these are stronger than dipole-dipole interaction. The strength of interaction falls off less rapidly with distance than for dipole-dipole interactions Induced dipole interactions Charge on one molecule induces dipole on another What is desolvation and what are - Desolvation is the removal of water so that our drug can the results of it? bind. - Desolvation requires water, and it is a necessary process, because the surrounding water molecules will weaken the interaction between ligand and target if the water is not removed. - Removing the water allows for interactions between the drug and its target to occur better. *However, stabilization energy that is gained by ligand-target interactions must be greater than energy penalty required for desolvation Also, remember that ∆𝐻 = 𝐸𝑏𝑟𝑒𝑎𝑘 − 𝐸𝑓𝑜𝑟𝑚 We need to have enough (+) interactions to outweigh the penalty of formation. We want delta H to be (-). Which regions are typically Polar regions. solvated? Hydrophobic interactions These regions of drug and target are not solvated. Interactions between hydrophobic regions of drug and target free up the ordered water molecules, thus increasing the entropy, increasing the ∆𝑆. Increasing delta S helps us to get a + value, and thus a (-) delta G according to the Gibbs free energy equation. Increased entropy increases spontaneity. As the Kd value becomes smaller, It increases what happens to the concentration of the receptor:ligand complex? Is covalent bonding reversible? no 3 List the steps of the composite 1. Bioactive conformation binding model 2. Removal of water (desolvation) 3. Ligand binds, providing free energy from interactions 4. Ligand dissociated 4