Section 5 Flashcards

Question

What is the difference between logP and logD?

Answer 1

LogP is used for neutral molecules. LogD is used for ionisable molecules and considers the effects of the ionisation of the molecule and changes in evironmental pH.

Answer 2

Steric parameter (Es) = measure of steric bulk of the R group based on their effect on the rate of ester hydrolysis, relative to that of the parent ester. Molar refractivity (MR) = measure of molecular volume and polarisability.

Answer 3

Determines the length of a substituent from the parent molecule (L) and the width from the plane in 4 directions (B1-4).

Answer 4

Hansch equation - uses linear multiple regression analysis considering size, lipophilicty, and electron characteristics to determine which congeners have impact on a target of interest. Free-Wilson (additivity) equation - assess additive substituent effects on the overall molecule, rather than component functional groups. It attempts to directly relate changes in structure to changes in activity, rather than in correlation to the physicochemical properties.

Answer 5

The ensemble of steric and electronic features that are necessary to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger (or to block) its biological response.

Answer 6

Receptor-excluded volume - the combined 3D volume of all active analogues which fit the pharmacophore model. Receptor-essential area - the combined extra volume of compounds which adhere to the pharmacophore but are inactive. Often these areas extend the boundaries of the binding pocket and sterically clash with the receptor.

Answer 7

Comparative Molecular Field Analysis. Comparative Molecular Similarity Index Analysis. Generate and superimpose low energy conformers of molecules with similar biological activity, with pharmacophoric element matching. For each conformer, the electrostatic and steric field is determined.

Answer 8

A stereoisomer produced by rotation about a sigma (σ) bond.

Answer 9

At distance sigma (the size of the atom), the potential energy is 0v. As they come closer, dipole-dipole interactions occur resulting in a slightly negative potential energy. As they get even closer, the attraction increases, resulting in more negative potential energy, until an optimum energy minimum value is reached (epsilon). If the atoms get any closer, the potential energy will start to increase back towards 0v as the overlap in atomic orbitals results in repulsive forces which forces them apart.

Answer 10

CoMFA models generate 2 maps: a steric plot, showing where steric bulk is desirable and undesirable, and an electronic plot, showing where electron rich and poor areas are optimal. CoMSIA considers size, electrostatic potential, hydrophobic properties, and H-bond donor/acceptor capability. There are maps: a steric plot, showing where steric bulk is desirable and undesirable, an electronic plot, showing where electron rich and poor areas are optimal, and a hydrophobic map, where hydrophobic and hydrophilic areas are optimal.

Answer 11

Cannabinoid receptor 1 (CB1R) is a G-coupled protein receptor activated by endogenous cannabinoids such as anandamine and 2-AG. Agonist binding results in signalling through a Gi cascade which causes inhibition of intracelullar adenylate and subsequent reduction in cAMP. In central CB1Rs (found in hypothalamus and nucleus accumbens), this drives feeding behaviour. In peripheral CB1Rs (adipose tissue, liver, GIT, muscle), this causes insulin resistance and increased triglycerides. Basically causes increased food intake and fat storage and weight gain, so inhibition would prevent it.

Answer 12

H-bond acceptors Aromatic rings Hydrophobic groups

Answer 13

1. Zinc acts as Lewis acid to activate phosphorous oxygen bond in phosphate of cGMP, make the phosphorous more electrophilic. 2. Lone pair on incoming water attacks electrophilic phosphorous atom. 3. Phosphorous-oxygen double bond opens up and then reforms as it pushes out the alkoxy (O-R) leaving group at the 3' position of the ribose ring, breaking this cyclic structure. 4. Outgoing alkoxy group picks up proton from adjacent His613 residue on enzyme. 5. This produces guanine monophosphate (GMP)

Answer 14

PDE inhibitors prevent degradation of intracellular messengers cAMP and cGMP, thus improving intracellular signalling. The result depends on which PDE isoform is targeted.

Answer 15

1. Excessive dopamine signaling in the striatum may directly lead to psychotic symptoms in schizophrenia. PDE10A found in striatum area of the brain and, due to impacts on cyclic nucleotides, impacts dopamine signalling. 2. Compound library screened in PDE10A affinity assay. Triaylimidazole 10 was identified. 3. Co-crystallisation of triaylimidazole 10 with PDE10A revealed interactions which explained its good affinity and high selectivity. 4. A second round of screening was performed to find compounds which: fit the selectivity pocket, could form H-bonds with Tyr-693, and obeyed certain physicochemical parameters which promote BBB permeability. Compound 11 identified. 5. Removal of a methylene group from compound 11 produced compound 12 which had a different orientation in the binding pocket resulting in an additional H-bond. This improved binding affinity, ligand efficiency, and reduced molecular weight. 6. Compound 12 undergoes in vivo conditioned avoidance response (CAR) test and does not perform well unless at extremely high concentrations. 7. Compound 12 optimised to produce Mardepodect.

Answer 16

1. Animal is conditioned by simultaneous exposure to the conditioning stimulus (e.g., a sound) and an unconditional stimulus (e.g., mild electric shock). 2. In response to unconditioned stimulus, the animal will try to escape/avoid it. In doing so, it will begin to associate the conditioning stimulus with this. 3. After this, exposure to only the conditioned stimulus will result in the same avoidance behaviour.

Answer 17

4-pyridine moiety. Methylation of pyrazole. Quinoline ring system.