Drug Mechanisms and Drug Resistance

Question 1

Energy of ionic bond

Answer 1

16-28 kJ/mol

Question 2

Energy of Van der Waals interaction

Answer 2

4 kJ/mol

Question 3

Nitrogen-hydroxyl hydrogen bond energy

Answer 3

28 kJ/mol

Question 4

Hydroxyl-oxygen hydrogen bond energy

Answer 4

20 kJ/mol

Question 5

Amine-nitrogen hydrogen bond energy

Answer 5

12 kJ/mol

Question 6

Amine-oxygen hydrogen bond energy

Answer 6

8 kJ/mol

Question 7

Thioester bond energy

Answer 7

31 kJ/mol

Question 8

Free energy of ATP hydrolysis

Answer 8

30 kJ/mol

Question 9

Free enery of phosphocreatine hydrolysis

Answer 9

44 kJ/mol

Question 10

ΔG from K_d

Answer 10

ΔG’^o = - RT ln(K_eq’)

K_eq’ = 1 / K_d

Ergo, alternatively:

ΔG’^o = RT ln(Kd)

Question 11

If K_d = 1 mM, ΔG’^o =

Answer 11

If K_d = 1 mM, ΔG’^o = -17 kJ/mol

Question 12

If Kd = 1 nM, ΔG’^o =

Answer 12

If Kd = 1 nM, ΔG’o = -51 kJ/mol

Question 13

If Kd = 1 μM, ΔG’^o =

Answer 13

If Kd = 1 μM, ΔG’^o = -34 kJ/mol

Question 14

ΔG’^o

Answer 14

pH = 7.00

[Components] = 1 mM

T= 25^oC or 298K

P = 1 atm

Question 15

R

Answer 15

8.314 J / mol K

Question 16

A drop in K_d by one order of magnitude (e.g., by 10^-3) corresponds to a change of ___ kJ/mol in ΔG’^o

Answer 16

A drop in K_d by one order of magnitude (e.g., by 10^-3) corresponds to a change of -17 kJ/mol in ΔG’^o

Question 17

What problem do proteases solve?

Answer 17

Hydrolysis of proteins is thermodynamically favorable, but kinetically extremely slow.

This is because water is a bad nucleophile and amide carbonyls are bad electrophiles.

Question 18

Hydrolysis by a protease occurs at the ___ bond

Answer 18

Hydrolysis by a protease occurs at the scissile bond

Question 19

Aspartyl protease mechanism

Answer 19

Question 20

Protease “flaps”

Answer 20

Question 21

Flap-peptide interaction

Answer 21

Question 22

Classes of HIV antivirals

Answer 22

Question 23

Actions of HIV protease

Answer 23

Question 24

HAART

Answer 24

Highly active antiretroviral therapy

• Combination of drugs targeting HIV at different stages in lifecycle
• Started as early as possible after diagnosis
• Latent virus cannot be eliminated, so treatment must continue for life

Question 25

HIV Reverse Transcriptase mutations providing protection against NRTIs and NNRTIs

Answer 25

Question 26

Mechanisms of HIV resistance to NRTIs

Answer 26

Question 27

Q151M complex

Answer 27

A set of 4 mutations in HIV reverse transcriptase that confers resistance to all currently FDA-approved NRTIs except tenofovir

Question 28

Mutations conferring resistance to retonvair

Answer 28

Question 29

Cross-resistance

Answer 29

Resistance to an antiviral to which a virus has never been exposed, as a result of mutations positively selected for by application of another antiviral

Always drug-class restricted. Often spans an entire drug class, but not always

Question 30

Methodology for testing LoF in aspartyl proteases

Answer 30

ASP → ASN directed mutagensis in active-site aspartates