Candidate No. . .

UNIVERSITY COLLEGE LONDON Seat No .

EXAMINATION FOR INTERNAL STUDENTS

MODULE CODE CHEMG204

ASSESSMENT CHEMG204B
PATIERN

MODULE NAME Principles of Drug Design

DATE 16 May 2017

TIME 2:30 pm

TIME ALLOWED 2 hours

This paper is suitable for candidates who attended classes for this
module in the following academic year(s):.

2016/2017

Under no circumstances are the

attached papers to be removed from
the examination by the candidate.

2016/17 ·CHEMG204B·001-EXAM-16
© 2016 University College London TURN OVER
 18
1 2
H He
1.0079 2 13 14 15 16 17 4.0026
3 4 5 6 7 8 9 10
Li Be B C N 0 F Ne
6.941 9.0122 10.811 12.011 14.007 15.999 18.998 20.180
11 12 13 14 15 16 17 18
~
~
Na Mg AI Si P S CI Ar ~ ~
:s ~
22.990 24.305 3 4 5 6 7 8 9 10 11 12 26.982 28.086 30.974 32.065 ~.., .
35.453 39.948
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 ~[
_... ()
K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga Ge As Sa Br Kr ~"n ::z::
39.098 40.078 44.956 47.867 50.942 51.996 54.938 55.845 58.933 58.693 63.546 65.38(2) 69.723 72.630 74.922 78.971 79.904 63.798
~~ m
(J= ~
37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 ::ro c:r
~
0. .
::: ~ ...
Rb Sr y Zr Nb Mo Te Ru Rh Pd Ag Cd In Sn Sb Te I Xe t:;" 0 ~
85.468 87.62 68.906 91.224 92.906 95.95 101.07 102.91 106.42 107.67 112.41 114.82 118.71 .:::- ~ --0
121.76 127.60 126.90 131.29 ~..... tl)
00cr (JQ
55 56 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 oo~ (D
~ N
Cs Sa 57~71 Hf Ta W Re Os Ir Pt Au Hg TI Pb Bi Po At Rn tv tfj 0
0\ .... .....,
132.91 137.33 178.49 180.95 183.64 186.21 190.23 192.22 195.08 196.97 200.59 204.38 207.2 208.98 v.. ~ ......
87 88 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 \O~
N= -
Fr Ra 89·103 Rf Db 59 Bh Hs Mt Os Rg Cn Nh FI Me Lv Ts Og -=
t3E:
o
0\

Lanthanoid 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 ---
series La Ce Pr Nd Pm 8m Eu Gd Tb Dy Ho Er Tm Yb Lu
138.91 140.12 140.91 144.24 150.36 151.96 157.25 158.93 162,50 164.93 167.26 166.93 173.04 174.97
Actinoid 89 90 91 92 93 94 95 96 . 97 98 99 100 101 102 103
series Ac Th Pa U Np Pu Am em Bk Cf Es Fm Md No Lr
232.04 231.04 238.03

-I
c:
:u
z
o
<
m
::D
 CHEMG204 page 3 of9

Fundamental Physical Constants

Reviews of Modem Physics 77, 1-107 (2005)

Quantity Symbol Value Unit

Pllysico-chemical constants
Avogadro constant NA,L 6.022 14 x 1023 mol-I
molar gas constant R 8.31446 J mol-I K- 1
Boltzmann constant R / N A k 1.380 65 x 10-23 J K- 1
Faraday constant N Ae F 9.648 53 x 104 C mol-I
Stefan-Boltzmann constant ()' 5.67037 x 10-8 W m-2 K-4
atomic mass constant mu 1.66054 x 10-27 kg

Atomic and nuclear constants

electron mass me 9.10938 x 10-31 kg
proton mass mp 1.672 62 x 10-27 kg
Rydberg constant R,., 1.09737 x 107 m- I
Bohr radius ao 5.291 77 x 10- 11 m
Hartree energy 2Roo hc Eh 4.53974 x 10-18 J
electron g factor ge -2.00232

Universal constants
speed of light in vacuum c,co 2.99792 x 108 ms- I
magnetic constant 41t x 10-7 f.lo 1.25664 x 10-6 N A-2
electric constant 1/f.lf,c2 £0 8.854 19 x 10- 12 Fm- I
gravitation constant G 6.674 08 x 10-11 m3 kg-I S-2

Planck constant h 6.62607 x 10-34 Js

11 =h/21C 1.054 57 x 10-34 Js

Electromagnetic constants
elementary charge e 1.602 18 x 10- 19 C
Bohr magneton eh/41tme f.lo 9.27401 x 10-24 J 11
nuclear magneton eh/41tm p f.lN 5.050 78 x 10-27 J 11

Adopted values
molar mass of 12C M( 12 C) 12 x 10-3 kg mol-I
standard acceleration of gravity gn 9.80665 ms-"-
standard atmosphere atm 1.013 25 x 105 Pa
electron volt eV 1.602 18 x 10-19 J

TURNOVER
 CHEMG204 page 4 of 9
Candidates should attempt ONE question from EACH section. Numbers in square brackets in the
right hand margin indicate the provisional allocation ofmarks to the subsections ofa question.

SECTION A
1. Answer ALL parts.
(a) For TWO of the enzyme inhibitors below state the biochemical transformation
induced by the inhibited enzyme, and identify the key mechanistic features
involved. Explain the mode of action of the inhibitor. [8]

o
Br~o,p:O
I \
NaO ONa

NS3 protease inhibitor A Triose phosphate isomerase inhibitor B

~O OH OH
~N N~C02H
H

F
HMG-CoA reductase inhibitor C

(b) Compound E is a potent inhibitor of the conversion of D into 2-C-methyl-D-

erythritol 4-phosphate (MEP) catalysed by the NADPH-dependent enzyme IspC
in the insect pathogen P. falciparum.
(i) Why might targeting the MEP pathway have potential for the treatment of
P. falciparum infections in humans? [2]
(ii) Giving molecular detail, account for (a) the binding of D in the active site
of IspC and (b) the inhibition of IspC by E. [5]

ft o 0

~
IspC PH II 1/
• HO'
. 0
..... P.,. . .
'OH HO.... N~(Ss. P.,......'OH
NADPH HO 'H OH Me ':oH OH
~ ~
o MEP
E

[Question 1 continued overleaf

TURN OVER
 CHEMG204 page 5 of9
Question 1 continued]
(c) Provide a mechanism for the inhibition of the flavin-dependent enzyme
monoamine oxidase A by F. [5]

Me d;
yyNJ NH ~O~N.....7
Enzs~N~NAo CI .& CI .
I
R
Flavin in monoamine oxidases F

2. Answer ALL parts.

(a) Methotrexate A interferes with DNA synthesis, is an anti-cancer agent, and also
exh.ibits weak antibacterial activity.

OMe

OMe
OMe
B

(i) Which enzyme is inhibited by methotrexate A? State whether the

inhibition is competitive, non-competitive or uncompetitive. [2]
(ii) Explain why methotrexate A is not a good lead compound for
antibacterial therapy. [2]
(iii) Compound B targets the same pathway as A. Explain why it would be a
better choice of lead compound. [3]
(b) State which enzyme is inhibited by antimicrobial compound C, and the function
of this enzyme. [3]
(c) Compounds D and E are useful in treating bacterial infections. Give detailed
mechanisms of action for BOTH B and C. [10]
oMe

'A o)=r-{<
~
I
OM. 0
H
N
H
:- S

C0 2 H
c o E

TURNOVER
 CHEMG204 page 6 of 9
SECTIONB
3. Compounds A to D were prepared as putative inhibitors of bacterial DNA gyrase, and
tested in an ill vitro assay which measures the inhibition of ATPase activity of the
isolated enzyme.

MeHNI(N'O
a I~
H

o I~
H
EIHNI(N'O PrHNI(N'O
a I~
H
EtHNI(N
o
H
'0
I~
A B C D
IC so =100 IlM IC so =30 IlM IC so >1000 IlM IC so >1000 IlM

(a) Provide plausible explanations for the change in ICso values across this series of
compounds, describing in detail any binding interactions that you mention. [9]
(b) Calculate the ligand efficiency of compound B and comment on this value. [2]
(c) Further optimisation led to the discovery of compounds E to G, with the data
shown below.

E (R = CaOH)
F (R = CONH 2)
G (R =CN)

E F G
logD7.4 0.6 2.0 2.8
solubility / J.lM 800 26 7.0
DNA gyrase ICso / J.lM 0.2 1.0 1.1

(i) Define logD7.4. Qualitatively, how would the logD of E change if

measured at lower pH? [5]
(ii) Although less potent in the enzyme assay, compounds F and G were more
potent than E in a cellular assay that measured the effect of each
compound on whole bacteria. Discuss and explain this apparent
inconsistency. [4]

TURNOVER
 CHEMG204 page 7 of 9

4. In a project to identify novel coagulants, compound A was identified as a highly potent

inhibitor of factor Xa. Compound A contains a benzamidine group with
pKaH =11.4, whereas compound B lacks a benzamidine group and is significantly less
potent.

B
FXa Kj =200 nM
(a) Calculate the proportion of neutral and charged forms of benzamidine A at
physiological pH = 7.4. [2]
(b) As observed for compound A, the benzamidine group is associated with poor oral
bioavailability. Suggest a possible explanation. [3]
(c) The benzamidine group in A binds strongly to a carboxylate group (Asp 189) in
factor Xa. Describe TWO interactions that could contribute to the strong binding
affinity observed. [5]
(d) Design TWO bioisosteres of the benzamidine group in A which might improve
its oral bioavailability. Explain how your suggestions could replicate either or
both of the possible interactions with Asp 189, and how bioavailability would be
affected. [l0]

TURNOVER
 CHEMG204 page 8 of 9
SECTIONC
5. Sofosbuvir is a treatment for the hepatitis C virus (HCV). Sofosbuvir is a prodrug. Data
for sofosbuvir and its monophosphate form are given below.

Sofosbuvir Monophosphate form

MW= 529.5 MW= 340.2
cLogP = 0.8 cLogP =-2.8
PSA = 152.7 A PSA= 145.sA

(a) Using detailed chemical structures, show the biochemical pathway by which
sofosbuvir is converted into its monophosphate form. [8]
(b) With the aid of structures, give the mechanism of action of sofosbuvir. [6]
(c) Explain why a prodrug form of the nucleoside monophosphate is necessary. Use
diagrams to illustrate your answer. [6]

TURNOVER
 CHEMG204 page 9 of 9
6. Data for the anti-cancer agent osimertinib are given below, together with its structure and
that of compound A.

Osimertinib A
MW = 449.6
=
cLogP 4.6
PSA = 84.8 A
=
pKa 9.6

(a) Explain with the aid of a detailed drawing the biochemical mechanism by which
osimertinib inhibits its protein target. [6]
(b) To which class of anti-cancer agent does osimertinib belong? [2]
(c) An initial low molecular weight hit, compound A, showed activity against a
diverse range of non-target proteins. Suggest a reason for this lack of selectivity. [4]
(d) State the rules and other features that can be applied to predict the extent of drug-
likeness of a compound. [4]
(e) Apply the rules and other features referred to in (d) to osimertinib and interpret
the results. Comment on any non-druglike features. [4]

END OF PAPER

END OF PAPER