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9.5.2 Agents acting on the HMG-CoA reductase
HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A reductase) is an enzyme responsi-
ble for catalyzing the synthesis of mevalonate in the body. Mevalonate is further re-
quired for the synthesis of sterols, including cholesterol, in the body. By inhibiting
HMG-CoA, the level of cholesterol is lowered as a pharmacological response.
Statins are the class of drugs that are used to inhibit this HMG-CoA reductase for
lowering the blood cholesterol level and are clinically prescribed for disorders like
diabetes mellitus, cardiovascular complications, and obesity. Common statins em-
ployed for this example are given in Tab. 9.3.
To understand the molecular interactions of the above statins against the HMG-
CoA, molecular docking was performed. The structure of the HMG-CoA was obtained
from the protein data bank (PDB ID: 1HWK) and the structures of the above-mentioned
statins were drawn through the molecular modeling software. All other steps for per-
forming molecular docking are similar as mentioned above. The results of our molecu-
lar docking are shown in Tab. 9.4.
From the results depicted in Tab. 9.4, it is clearly understood that all of the three
mentioned statins show similar types of binding energy with the HMG-CoA. They dif-
fer in their interaction with the HMG-CoA in the number and type of H-bonding and
hydrophobic interactions. Amino acid residue, ASN-755, shows hydrogen-bonding in-
teractions with all of the three statins. LYS-692 and SER-684 are common interacting
amino acids between lovastatin and rosuvastatin. Amino acid, ARG-590, is common
between rosuvaststin and atorvastatin. The molecular interaction images of all three
statins are given in Fig. 9.9.
Tab. 9.2: Results of the molecular docking study.
S. no. Ligand Receptor Dock
score
(kcal/mol)
No. of
H-bonds
Amino acids
involved in
H-bonding
Amino acids involved in
hydrophobic interactions
Trimethoprim XG −. GLY-
TYR-
ALA-
THR-
ILE-
ILE-
ALA-
Pyrimethamine BL −. SER-
SER-
ILE-
ALA-
PHE-
CYS-
Methotrexate RG −. NIL NIL LEU-
LYS-
ILE-
PHE-
9.5 Some examples of molecular docking 209
a) Methotrexate b) Trimethoprim
c) Pyrimethamine
Fig. 9.8: The molecular docking interaction diagram of the binding of trimethoprim, pyrimethamine, and
methotrexate with the dihydrofolate reductase (DHFR) enzyme.
Tab. 9.3: List of molecules tested against HMG–CoA.
S. no. Name and structure of ligand (drug)
Lovastatin
210 Chapter 9 Molecular docking and drug–receptor interactions
Tab. 9.3 (continued)
S. no. Name and structure of ligand (drug)
Rosuvastatin
Atorvastatin
Tab. 9.4: Results of the molecular docking study.
S. no. Ligand Dock
score
(kcal/mol)
No. of
H-bonds
Amino acids
involved in H-bonding
Amino acids involved in
hydrophobic interactions
Lovastatin −.HIS-
ASN-
SER-
LYS-
NIL
Rosuvastatin −.ARG-
SER-
LYS-
LYS-
ASN-
LYS-
ALA-
LEU-
Atorvastatin −.GLU-
ASP- ()
ASN-
ARG- ()
SER-
LEU-
VAL-
ALA-
ALA-
9.5 Some examples of molecular docking 211
9.5.3 Agents acting on HIV-protease
HIV protease is a key enzyme required by the human immunodeficiency virus (HIV) for
its replication. Blocking these protease enzymes results in the inhibition of viral replica-
tion inside the human body and hence, reducing the virus load to the desired value.
Therefore, use of HIV protease inhibitors is an important strategy in anti-HIV therapy.
Some of the important drugs marketed under this category are given in Tab. 9.5. Inter-
estingly, the discovery of these protease inhibitors is credite d to molecular docking
studies.
b) Saquinavir
c) Indinavir
a) Lopinavir
Fig. 9.9: The molecular docking interaction diagram of the binding of lovastatin, rosuvastatin, and
atorvastatin with the HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase enzyme.
212 Chapter 9 Molecular docking and drug–receptor interactions
Tab. 9.5: List of molecules tested against HIV.
S. no. Name of drug
Saquinavir
Indinavir
Lopinavir
9.5 Some examples of molecular docking 213
The molecular docking of these protease inhibitors was performed using the HIV pro-
tease enzyme (PDB ID: 3OXC). By using the steps mentioned above for the molecular
docking, the results are depicted in Tab. 9.6.
From the above results, it is evident that all three protease inhibitors are highly
potent as they show excellent binding affinity with the receptors. Saquinavir demon-
strated the highest binding in terms of binding energy (−11.5 kcal/mol) as well as the
number of hydrogen bond interactions (four). Among the amino acid residues, GLY-48
is observed to be the common amino acid showing hydrogen bonding interaction
with Saquinavir and Lopinavir. The molecular interaction images of these drugs
docked with the protease enzyme are shown in Fig. 9.10.
9.5.4 Agents acting on acetylcholinesterase (AChE)
Acetylcholine (ACh) is a neurotransmitter that is broken down by the AChE enzyme
into acetate and choline part. During Alzheimer’s disorder, there is a degeneration of
cholinergic neurons resulting in impaired cholinergic signaling. Therefore, inhibiting
AChE results in the increased concentration of ACh in synapses and consequently im-
proved cholinergic signaling during Alzheimer’s disorder. Some of the clinically used
drugs for inhibiting this AChE enzyme are given in Tab. 9.7.
Tab. 9.6: Results of the molecular docking study.
S. no. Ligand Dock
score
(kcal/mol)
No. of
H-bonds
Amino acids
involved in H-bonding
Amino acids involved in
hydrophobic interactions
Saquinavir −.ASP-
GLY-
GLY-
ILE-
ALA-
ILE-
PRO-
VAL-
Indinavir −.ASP-
GLY-
PRO-
VAL-
ALA-
ALA-
ILE-
Lopinavir −.GLY-
GLY-
ILE-
VAL-
ALA-
ILE-
ILE-
ILE-
ALA-
VAL-
214 Chapter 9 Molecular docking and drug–receptor interactions
b) Rosuvastatin
c) Atorvastatin
a) Lovastatin
Fig. 9.10: The molecular docking interaction diagram of the binding of saquinavir, indinavir, and lopinavir
with the HIV-protease enzyme.
Tab. 9.7: List of molecules tested against AChE.
S. no. Name of drug
Rivastigmine
9.5 Some examples of molecular docking 215
The molecular docking studies of the above AChE inhi bitors were performed on the
AChE enzyme (PDB ID: 1 GQR). The results of the molecular docking simulations are
summarized in Tab. 9.8.
Tab. 9.7 (continued)
S. no. Name of drug
Physostigmine
Donepezil
Tab. 9.8: Results of the molecular docking study.
S. no. Ligand Dock
score
(kcal/mol)
No. of
H-bonds
Amino acids
involved in H-bonding
Amino acids involved in
hydrophobic interactions
. Rivastigmine −.TYR-
SER-
TRP-
TYR-
PHE-
TYR-
. Physostigmine −.HIS-
ARG-
TYR-
PHE-
TYR-
. Donepezil −.SER- ()
GLY-
PHE-
TYR-
TYR-
LEU
TRP-
TRP-
216 Chapter 9 Molecular docking and drug–receptor interactions
From the results depicted in Tab. 9.8, it is evident that donepezil shows the best bind-
ing affinity (−11.8 kcal/mol) with AChE, followed by physostigmine (−8.8 kcal/mol), and
rivastigmine (−7.8 kcal/mol) (Fig. 9.11).
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Fig. 9.11: The molecular docking interaction diagram of the binding of the rivastigmine, physostigmine,
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