University Chemistry: Data Analysis and Pharmacophore Modeling

This chemistry assignment solution analyzes experimental procedures and data related to chemical reactions and pharmacophore modeling. It covers the synthesis of a compound, including safety precautions, and interprets NMR spectra, focusing on coupling constants and signal origins. The assignment further examines the interaction of inhibitors with the CYP3A4 enzyme, including hydrophobic contacts, pi-interactions, and hydrogen bonds, using a pharmacophore model. The analysis involves the IC50 values of different compounds and their potential as CYP3A4 inhibitors, along with a discussion on the mechanism-based inhibition of cytochrome CYP3A4 by drugs like erythromycin. The solution references relevant scientific literature to support the analysis.

Running head: ANALYSIS OF DATA
ANALYSIS OF DATA
Name of the Student
Name of the University
Author note

1ANALYSIS OF DATA
Answer 3
a) The experimental procedure need to be followed
2-Brooacrylic acid present in flask and thioacetanilide was added into the flask with drops of
toluene. The reagent was mixed and the flask was heated in water bath around a temperature of
90oC for 10 mins. The flask will be removed and allowed to cool down at room temperature.
After the temperature gets back to normal acetone was added for further reaction. The sample
would let standstill so that crystallization occurs.
The safety precaution to be taken while performing the reaction are-
As compound C are harmful hence the protection need to be worn. Compound C is considered
toxic therefore the synthesis would be performed in a protected environment. Toxic compound
causes skin corrosion along with eye damage and respiratory irritation it is recommended to wear
gloves, glass goggles as well as masks. Face protection are required to handle toxic chemicals. If
there is any accident the person must be moved immediately to fresh air and must be washed
thoroughly with water and call for poison centre or doctor if the person feels sick or uneasy.
b i)
Fig 1a: representing H3 between 7.41 to 7.38. (arrow sign marks the location)

2ANALYSIS OF DATA
Fig 1b: representing H3 between 7.41 to 7.38 only.
ii) The signals originated at the H-atom of the compound. CDCL3 consists of H2O as
preservative. The H2O have the capability to exchange with the recognised compound. Hence
anhydrous CDCL3 are formed however decomposition occurs when the compound gets exposed
to generate DCL, causing the speeding up of the exchanges of signals for OH as well as NH.
Therefore, it is not observed in the spectrum.
iii) Coupling rises due to the magnetic field of nearby protons, which effects the arena
experienced by proton. The compound has both CH as well as –CH3 group. The -CH group has
the ability to accept two alignments according to applied field (Khachatryan et al. 2015). The
coupling constant J measures the interactions among pairs of proton. Hence, it analysed that for
the compound Ha-C-C-Hb the coupling of Ha along with Hb, Jab, need to be identical for the
coupling of Hb along with Ha, Jba. Hence, Jab is equal to Jba. This coupling constant is
characteristically about 6-8 Hz. Coupling is measured by geometry in addition to the orbitals that
are intricate among the coupling nuclei besides other categories of structures have marginally
dissimilar coupling constants (Grozdano and van der Schee 2017)

3ANALYSIS OF DATA
Fig 2: Coupling Constant (Grozdano and van der Schee 2017)
Answer 4
(I have inserted the same value in the table, please check the file attached with this paper)
a) 6BCZ
hydrophobic contact: PHE 213-PHE241, PHE213-PHE304, ILE301-PHE304, THR309-ILE369
Pi-interactions: PHE108 - R1 (π- cation)
H-bonds: ILE301-ALA305, ALA305-THR309, ALA370-ARG372
6BD7
Hydrophobic contact: PHE108-PHE213, PHE213-R1, PHE108, PHE108-R1, PHE213-PHE241,
PHE241-PHE241, PHE213-PHE304, ILE120-R1, ILE120-ILE301, ALA370-R1, ILE369-R1,
ALA305- R1, THR309- R1, GLU374- R1
pi-interaction: No protein residues
hydrogen: ILE301-HEM305, SER119- R1, GLU374- ARG106, ALA370-ARG372
6BDI
Hydrophobic: table data
Pi-interaction: no protein residues

4ANALYSIS OF DATA
Hydrogen: ILE301-ALA305, ALA305-THR309
b) A pharmacophore model is the collective of mutual steric as well as electronic structures that
are essential to safeguard the optimal molecular connections with a certain biological objective
and to generate (or block) its biological response (Kaur et al. 2016). The IC50 value of
compound 1 is found to be highest whereas the IC50 value is lowest for rotanavir and for
compound 3 is also low. The compound has all the bonds such pi bond, hydrogen as well as
hydrophobic bonds whereas compound 3 and 2 do not have pi-interaction. This suggests that
compound 1 is less potent as a drug. As lesser the IC50 of the drug, a smaller amount need to be
achieved the anticipated effect. The study through pharmacophore model determines the
electronic and steric features which are required for optimal molecular interactions and also to
trigger biological responses. Hence, compound 3 as well rotanavir are potential inhibitor
(Bhattacharjee et al. 2015).
c) Mechanism-based inhibition of cytochrome CYP3A4 is categorised by NADPH, absorption
dependant enzyme inactivation as well as time. Erythromycin is a moderate CYP3A4 inhibitor
(Denisov et al. 2015). Few drug have the ability to be improved by CYPs to responsive
metabolites. Erythromycin inhibitions of CYP3A4 are due to the chemical alteration of the
protein the heme, due to of covalent binding of altered heme to the protein. Though
erythromycin modestly decreases drug clearance clearance, it led to affiliated increase of the
absorptions of pharmacologically active metabolite (Henderson et al. 2015). The inactivation of
CYP3A4 by drugs is essential as the clinical connotation as it break down roughly 60% of
therapeutic drugs, in addition to its inhibition repeatedly develops unfavourable drug–drug
interactions along with toxicity. The clinical consequences are due to CYP3A4 inactivation as it

5ANALYSIS OF DATA
depends on several factors linked with the patient, enzyme and drugs (Towles et al. 2016). A
new theory that includes drugs which are mechanism-based CYP3A4 inhibitors.
References
Bhattacharjee, A.K., Marek, E., Le, H.T., Ratcliffe, R., DeMar, J.C., Pervitsky, D. and Gordon,
R.K., 2015. Discovery of non-oxime reactivators using an in silico pharmacophore model of
reactivators for DFP-inhibited acetylcholinesterase. European journal of medicinal chemistry,
90, pp.209-220.
Denisov, I.G., Grinkova, Y.V., Baylon, J.L., Tajkhorshid, E. and Sligar, S.G., 2015. Mechanism
of drug–drug interactions mediated by human cytochrome P450 CYP3A4 monomer.
Biochemistry, 54(13), pp.2227-2239.
Grozdanov, S. and van der Schee, W., 2017. Coupling constant corrections in a holographic
model of heavy ion collisions. Physical review letters, 119(1), p.011601.
Henderson, C.J., McLaughlin, L.A., Scheer, N., Stanley, L.A. and Wolf, C.R., 2015. Cytochrome
b5 is a major determinant of human cytochrome P450 CYP2D6 and CYP3A4 activity in vivo.
Molecular pharmacology, 87(4), pp.733-739.
Kaur, P., Chamberlin, A.R., Poulos, T.L. and Sevrioukova, I.F., 2016. Structure-based inhibitor
design for evaluation of a CYP3A4 pharmacophore model. Journal of medicinal chemistry,
59(9), pp.4210-4220.
Khachatryan, V., Sirunyan, A.M., Tumasyan, A., Adam, W., Bergauer, T., Dragicevic, M., Erö,
J., Fabjan, C., Friedl, M., Frühwirth, R. and Ghete, V.M., 2015. Measurement of the inclusive 3-
jet production differential cross section in proton–proton collisions at 7 TeV and determination
of the strong coupling constant in the TeV range. The European Physical Journal C, 75(5),
p.186.

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Towles, J.K., Clark, R.N., Wahlin, M.D., Uttamsingh, V., Rettie, A.E. and Jackson, K.D., 2016.
Cytochrome P450 3A4 and CYP3A5-catalyzed bioactivation of lapatinib. Drug Metabolism and
Disposition, 44(10), pp.1584-1597.