05b9a96b-b5cb-4def-8338-db99e6b787d9_135151_-_isaac

Latest published:

16 Oct 2023,

:1332

Creative Commons Attribution

Abstract

Introduction

: Insomnia is a condition that affects the quality of life of

an individual. It is associated with a lack of sleep or interrupted sleep.
If not managed, insomnia may end up causing conditions such as
obesity, heart conditions, hypertension, and mental disorders. Lack of
sleep is also associated with an increased risk of Alzheimer’s disease.
There is, therefore, a need to develop a drug that manages insomnia
with desirable clinical outcomes

Methods

: The canonical smiles of Zolpidem, Suvorexant, Ramelteon,

and Triazolam were obtained from PubChem. The study used the
online tool SwissSimilarity to identify structural analogs for Zolpidem,
Suvorexant, Ramelteon, and Triazolam. The canonical smiles were
copied to PubChem Sketcher were converted to a 2- dimensional (2D)
format. The Avogadro was used to optimize the ligands. The
respective receptors were obtained from the Protein Data Bank.
Chimera was used to prepare the receptor and the docking, using
AutoDock Vina. SwissADME and Protox server was used in the
determination of the pharmacokinetics and toxicity profiles,
respectively.

Results

: Docking scores, pharmacokinetics, and toxicity profiles of the

analogs were recorded. Nine structural analogs from the ZINC
database (ZINC000004222622, ZINC000003981996,
ZINC000003825731, ZINC000000000903, ZINC000039247014,
ZINC000010152022, ZINC000000347721, ZINC000065743121
ZINC000022054496) were found to have a better docking score, blood
brain barrier permeability, Lipinski’s violations, synthesizability index,
gastrointestinal tract absorption, p-glycoprotein substrate metabolism
LD50 compared to the parent drug molecules. All the nine molecules

Open Peer Review

Approval Status

version 1

16 Oct 2023

view

Khaled Darwish

, Suez Canal University,

Ismailia, Egypt

Any reports and responses or comments on the
article can be found at the end of the article.

Page 1 of 18

F1000Research 2023, 12:1332 Last updated: 12 MAR 2024

Corresponding author:

Isaac Oronyi (

isaac.oronyi50@gmail.com

)

Author roles:

Oronyi I

: Conceptualization, Data Curation, Investigation, Methodology, Resources, Software, Writing – Original Draft

Preparation, Writing – Review & Editing;

Kagia R

: Project Administration, Supervision, Validation, Writing – Review & Editing

Competing interests:

No competing interests were disclosed.

Grant information:

The author(s) declared that no grants were involved in supporting this work.

Copyright:

License

, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite this article:

Oronyi I and Kagia R.

Developing potential drugs for insomnia through computational analysis [version 1;

peer review: 1 approved with reservations]

F1000Research 2023,

:1332

First published:

16 Oct 2023,

:1332

https://doi.org/10.6084/m9.figshare.

had good synthesizability index, gastrointestinal absorption and zero
Lipinski violations indicating good oral availability.

Conclusions

: Ramelteon analogs ZINC000004222622,

ZINC000003981996, and ZINC000003825731, Triazolam drug-like
molecules, ZINC000000000903, ZINC000039247014,
ZINC000010152022, and ZINC000000347721 and Zolpidem drug-like
molecules ZINC000065743121 and ZINC000022054496 were identified
as the best compound bases on the pharmacokinetic binding to the
respective receptors and toxicity profiles.

Keywords

Insomnia , Computational analysis , MTR – Melatonin Receptor ,

CYP450 - Cytochrome P450, GABA - Gamma-Aminobutyric Acid , FDA-

Food and Drug Administration CNS -Central Nervous System.

This article is included in the

Bioinformatics

gateway.

Page 2 of 18

F1000Research 2023, 12:1332 Last updated: 12 MAR 2024

Introduction

Sleep is considered an essential component of both physical and mental health. Sleep is especially important in the
development of the immune system restoration, regulation of emotions, support of cognitive function in human learning,
and brain recuperation processes.

It is recommended that adults sleep for about seven to eight hours a day while in

infants, sleeping hours may be increased up to between 14 and 17 hours a day.

Sleep deprivation, is associated with

physical and mental disorders that may eventually lead to conditions such as weight gain, heart disease, and diabetes.

Lack of sleep has also been associated with suicidal ideation.

Sleep also helps with the clearance of toxic materials from

the brain through the glymphatic system.

This system works 20 folds during sleep than when an individual is awake.

Alzheimer

’

s is believed to be caused by toxic materials such as amyloid and tau proteins.

Lack of adequate sleep is

considered a risk factor for Alzheimer

’

s disease.

Insomnia is a condition in which an individual complains of a lack of sleep. These individuals have difficulty in the
initiation and maintenance of sleep.

Insomnia is a condition that affects an individual

’

s psychological, physical,

biological, and social well-being.

About one-third of the adult population presents with a symptom of insomnia.

It is more prevalent in women compared to men.

Individuals who are prone to conditions such as anxiety and those taking

certain medication such as antiretrovirals may be disposed of this condition.

Insomnia can lead to conditions such as

depression, coronary heart disease, hypertension, diabetes, and severe migraine.

Insomnia has also been indicated as a

major cause of atrial fibrillation in postmenopausal women.

Insomnia can be broadly classified into chronic and acute insomnia.

Acute insomnia is short-term, it can be caused by

factors such as a change in environment or even stress related and may only last for days.

On the other hand, chronic

insomnia is described as the lack of sleep for more than three weeks.

In chronic insomnia, may predispose an individual

to psychiatric disorders such as anxiety and depression.

Symptoms may differ from children to adults with adults more

likely to experience more problems related to problem maintaining sleep than problem associated to starting sleep.

Environmental factors such as exposure to stressors such as light, poor quality of air, and noise are common causes of
insomnia.

In the world of industrialization, people are migrating from rural areas to cities or towns for employment and

personal reasons.

With every country aiming to become industrialized, sound air and light pollution would be a

common manifestation.

The extremities of weather conditions may cause serious sleep-related disorders. This may be a

result of interference with the normal rhythm that controls the sleep cycle.

The current management of insomnia is based

on nonpharmacological and pharmacological interventions. These therapies may be limited based on the tolerance, side
effects and the suitability of the given drug for the patient.

Prescription drugs such as antidepressants, stimulants, bronchodilators such as theophylline, steroids, diuretics

and

some antiretroviral such as efavirenz,

may present with insomnia as a side effect. The regimen may be designed for

twice or three times daily. The patient may need to take the medication every eight hours or 12 hours respectively within a
24-hour interval which may end up interfering with sleep patterns.

Short acting benzodiazepines and hypnotics are also

associated with rebound insomnia as a as a result of chronic use of the drugs.

Pharmacological treatment of insomnia is aimed at improving the quality of sleep. Currently, the European sleep research
society has approved guidelines that are used in the treatment of insomnia.

The classes of drugs in the treatment of

insomnia include melatonin receptor agonists, benzodiazepine receptor agonists, anti-depressants and some first-
generation antihistamines.

Benzodiazepine receptor agonists work by binding to the gamma-aminobutyric acid (GABA) receptor. The drugs act as
positive allosteric modulators increasing the inward flow of chloride ions. This causes depression of the central nervous
system causing sleep.

The GABBA receptor agonists include both benzodiazepines and the non-benzodiazepines, such

as the Z-compounds; Zolpidem and Zaleplon. Quazepam is an The Food and Drug Administration (FDA)-approved
benzodiazepine used in the treatment of chronic insomnia. Triazolam, Flurazepam, and Temazepam have been indicated
in the treatment of sleep-onset insomnia. Temazepam is the most prescribed drug for insomnia.

Benzodiazepines are

common for abuse. For example, Flurazepam has been used in crime for stupefying people.

These drugs are also

associated with tolerance and these drugs are not advised to be given to patients during pregnancy.

Zolpidem has been associated with increased orthostatic hypotension in hospitalized patients, confusion, dizziness,
suicidal ideation, rebound insomnia, and daytime sedation.

It has been categorized in class C. Women in pregnancy are

at risk of getting children with a low weight if they take Zolpidem during pregnancy.

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F1000Research 2023, 12:1332 Last updated: 12 MAR 2024

Zaleplon is available as intravenous and oral preparations. Has the same side effects as zolpidem but has high incidences
of hallucination and hypersensitivity

The dose should also be decreased in the elderly because of their slow

metabolism.

Antihistamine drugs are also another group of drugs used in the treatment of insomnia. The commonly used drugs include
diphenylamine, doxylamine, and chlorpheniramine. They work by H1 receptor antagonism.

Their application utilizes

the side effect associated with first generations of antihistamines which is sedation. Although they are usually sold over
the counter, these drugs are characterized by rapid tolerance and possible anticholinergic side effects such as urinary
retention dry mouth, confusion, and constipation which may become worse as the dose is increased to obtain the desired
effects.

Their rapid availability over the counter commonly allows misuse. They are not preferred as first line treatment

because they are contraindicated in patients with concurrent medical conditions glaucoma, asthma, and bladder
obstruction.

Melatonin receptor agonists are drugs that work by the activation of the melatonin receptors M1 and M2. Melatonin
regulates the sleep-wake cycle and at the same time reproduction activities and growth that commonly happens during
sleep.

The common drugs that have been used include Ramelteon and Melatonin. Others include Tasimelteon and

agomelatine. Melatonin is rarely used because of the short duration of action.

Ramelteon binds to MTR1 and MTR2, this causes a reduction sleep-onset latency, slightly improve sleep efficiency and
increase total sleep time.

Although ramelteon has been described as not tending to cause tolerance and rebound

insomnia, clinical trials did prove that ramelteon dosage at 8 milligrams may cause, retropharyngeal pain, depression
galactorrhea, decreased libido, upper respiratory tract infections and exacerbated insomnia. This drug is also expensive
and hence not readily available.

Orexin receptor antagonist suvorexant approved in the year 2014, and was first marketed for insomnia.

Orexin receptor

antagonists influence patient wakefulness and sleep. The antagonism of this receptor is associated with decreased
wakefulness.

Although the medication does not need adjustment in patients with renal and hepatic insufficiencies, the

drug is a category c medication. The adverse effects are limited as compared to other drugs used for insomnia but the drug
is comparatively costly.

Doxepin is a tricyclic anti-depressant. It has been approved for the treatment of insomnia based on its activity on the H1
receptor is associated improvement of sleep latency.

It is a category C drug, with wide metabolism by the CYP2D6 and

CYP2C19 enzymes. This property makes the administration of the drug hard with drugs that are inhibitors or inducers of
those enzymes. Patients on doxepin may also experience allergic reactions.

Drug development involves analyzing vast libraries of compounds for their capacity to bind to a target protein. Preclinical
testing, clinical trials, and identifying possible drug candidates are all steps in drug discovery and development.

Virtual

screening is a computational technique used in drug development to find prospective therapeutic candidates. Ligand-
based virtual screening is a subset of virtual screening that looks for novel ligands with similar binding properties using
the 3D structure of an existing ligand.

This technique has been used in the discovery of drugs that are currently or

being studied in use in conditions such as COVID-19, cancer, and Alzheimer

’

s disease.

There is a gap in drug

development through virtual screening in the development of insomnia drugs.

This study works in line with the currently ongoing research for a drug that is most effective in the treatment of insomnia.
Zolpidem, suvorexant, ramelteon, and triazolam are analyzed. The aim is to get a drug that can be given to patients in such
a way the patient could continue their current medications and at the same time have a good sleep hence, the drug should
have very few interactions with the drugs in concurrent use. The drugs should be effective in the lowest concertation given
to patients suffering from insomnia. This means the drugs should then have a better docking score compared to the current
drugs used. The drugs should also have minimal side effects. The drug should also be effective in insomnia related
to environmental changes. It should also be able to treat the condition completely and treat the patient with the fewest
doses possible. The drug should also be safe to use during pregnancy. In general, we aim at getting a drug with better
pharmacokinetics pharmacodynamics, and pharmacogenomics compared to the current drugs in use.

Methods

Retrieving the drug models

The canonical smiles of Suvorexant, Ramelteon, Zolpidem and Triazolam were individually searched and copied from

PubChem

online library (RRID:SCR_004284). The Canonical smiles obtained were pasted into the

SwissSimilarity

search bar. The class of drugs was set as commercial. The combined, Zinc-Drug like was selected with combines 2D and

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F1000Research 2023, 12:1332 Last updated: 12 MAR 2024

3D. This was used as a query to generate similar molecular structures from the ZINC database through ligand based
virtual screening. The red search button of the page was clicked to allow the query to begin, which took a few minutes to
generate the final results. The generated results were downloaded and saved as an excel file.

Retrieving and preparation of the retrieving the protein models

The receptors were obtained from the

protein data bank

GABA-A receptor, Orexin receptor, and melatonin receptor were

individually searched on

protein data bank

(RRID:SCR_012820) search bar and downloaded using the

‘

Download file

’

option available on the Protein Data Bank. The receptors were saved in the project directory. The receptors were

“

Cleaned

”

by removing all non-standard compounds by clicking on the

“

Select

”

option on chimera, then selecting all

non-standard compounds, and finally deleting using the

‘

Actions

’

option on chimera software (RRID: SCR_004097).

Ligand preparation

The first 20 canonical smiles of each parent drug compound, were pasted in the search bar at

PubChem Sketcher

and enter

button clicked to allow the generation of a to a 2D molecular structure. The generated structure was saved as

“

All files

”

format by clicking the export button present in

PubChem Sketcher

to the Project folder in the desktop.

PubChem Sketcher

was refreshed before the next canonical smile was inserted for the next query.

The Avogadro software (RRID: SCR_011958) was opened. The software was used to open the 2D files which were
generated from the project folder in the Desktop. The 2D structures of the analogs and the drug compounds were
converted to 3D structures automatically, by opening them individually, and clicking

“

yes

”

on the prompt by Avogadro to

generate a 3D model of the 2D structure that was being opened. The 3D generated structure was optimized by clicking the
auto optimization option provided in Avogadro. The settings were set to MMF94s force field, and fixed atoms movable,
on the Algorithm settings. The start button was clicked and the structure was allowed to form the most stable
conformation. The most stable conformation was determined when the Auto optimization energy became constant.
The resulting structure was saved as a.mol file to be used in the next step in chimera.

The optimized ligands were then opened and minimized (to add charges and hydrogen) using the Chimera software.
This was done by clicking tools, then structure editing, using the steric only settings and then Gasteiger as the other
residues, in the setting section. The resulting minimized structure was saved in the project folder to for the next process of
docking

Docking

The minimized ligands and the cleaned receptor were opened simultaneously in Chimera. The docking process was
initiated where the ligands were docked with their respective receptors using the chimera software, embedded with
AutoDock Vina (RRID: SCR_011958). The docked compounds with better docking scores than the parent compounds
were afterwards analyzed using the Biovia Discovery studio (RRID: SCR_01565) to determine the interaction between
the receptor and the ligand using the 2D and 3D models of the complexes.

Determination of the pharmacokinetic properties

The canonical smiles of compound found to have a better docking score than the parent compounds were pasted on

SwissADME

online tool search box and queried to determine possible pharmacokinetic properties. The results were

saved as an excel file. The results contained parameters such as Blood brain barrier permeability, the Lipinski

’

violations, Gastrointestinal tract absorption, p-glycoprotein substrate, metabolism and synthesizability index which
were used in the study.

Determination of the toxicity profile

The

Protox

online tool was used to predict the toxicities of the compounds. The canonical smiles of the parent drug

compounds and the analogues were pasted individually on the search bar in the Protox server and queried for the toxicity
profiles prediction. The parameters that were analyzed included the individual toxicities based on the LD50 were
automatically generated with the

Protox

which was directly obtained from the search results.

Data presentation

Tables of the specific analogues (

and

) were recorded showing various data obtained.

The data include the docking scores, the pharmacokinetic profile, and the toxicities profile.

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F1000Research 2023, 12:1332 Last updated: 12 MAR 2024

Table

Suvorexant

and

its

analogs

pharmacodynamic

and

toxicity

data.

Compound

Docking

scores

LD50

(mg/kg)

Blood

brain

barrier

permeant

Gastrointestinal

absorption

P-glycoprotein

substrate

Metabolism

Lipinski

violations

Synthetic

accessibility

Suvorexant

-9.2

1000

High

CYP

(2C19,2C9,

2C19)

3.97

ZINC000049036447

-10.6

1190

High

CYP

(2C9,

2C19,3A4)

3.97

ZINC000095079930

-10.0

1190

High

CYP

(2C9,

2C19

2D6,3A4)

3.97

ZINC000253476142

-9.8

1190

High

CYP

(2C9,

2C19,3A4)

3.96

ZINC000206774725

-9.3

1190

Yes

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

3.34

ZINC000206770769

-9.6

1000

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

3.44

ZINC000206774070

-9.8

1000

Yes

High

Yes

CYP

(2C9,

2C19

2D6,3A4)

3.51

ZINC000206774330;

-9.3

1190

Yes

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

3.46

ZINC000253409176

-9.8

1190

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

3.95

ZINC000253409179

-9.7

1190

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

3.95

ZINC000206774469

-3.8

1190

Yes

High

Yes

CYP

(1A2,2C9,

2C19

2D6,3A4)

3.63

ZINC000253409181

-9.9

1190

Yes

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

3.36

ZINC000253409181

-9.5

1190

High

CYP

(2C9,

2C19

2D6,3A4)

3.95

Page 6 of 18

F1000Research 2023, 12:1332 Last updated: 12 MAR 2024

Table

Ramelteon

and

its

analogs

pharmacodynamic

and

toxicity

data.

compound

Docking

scores

(mg/kg)

Gastrointerstinal

absorption

Blood

brain

barrier

permeant

P-glycoprotein

substrate

Metabolism

Lipinski

volations

Synthetic

accessibility

Ramelteon

-7.8

1000

High

Yes

CYP(2C19,2D6)

2.91

ZINC000000007031

-8.5

1190

HIGH

Yes

CYP(2C19

2D6)

2.91

ZINC000003960339

-8.8

860

HIFH

Yes

CYP(2D6)

2.81

ZINC000003981996

-7.9

860

HIGH

Yes

CYP(2D6)

2.96

ZINC000003825731

-8.5

860

HIGH

Yes

CYP(2D6)

2.45

ZINC000068741265

-8.7

1190

HIGH

Yes

CYP

(1A2,2C9,

2C19

2D6)

2.02

ZINC000068741252

-8.5

1190

HIGH

Yes

CYP

(1A2,2C9,

2C19

2D6)

2.18

ZINC000068741294

-8.0

860

HIGH

Yes

CYP(2D6)

2.58

ZINC000225596222

-8.3

860

HIGH

Yes

CYP

(2C9,

2C19,2D6)

2.68

ZINC000225596523

-8.6

860

HIGH

Yes

CYP

(2C19

2D6)

3.36

ZINC000004222632

-8.5

860

HIGH

Yes

CYP

(2C9,

2D6,3A4)

3.36

ZINC000225596253

-9.1

860

High

Yes

2C19,2D6

2.68

ZINC000225600895

-8.3

2000

High

Yes

CYP(1A2,2C19,2D6)

2.65

ZINC000004222622

-8.7

860

High

Yes

CYP(2D6)

3.28

Page 7 of 18

F1000Research 2023, 12:1332 Last updated: 12 MAR 2024

Table

Triazolam

and

its

analogs

pharmacodynamic

and

toxicity

data.

Compound

Docking

scores

(mg/kg)

Gastrointestinal

absorption

Blood

brain

barrier

permeant

P-glycoprotein

substrate

Metabolism

Lipinski

violations

Synthetic

accessibility

Triazolam

-8.1

695

High

Yes

CYP

(1A2,2C9,

2C19)

3.37

ZINC000000002212

-8.5

1080

High

Yes

CYP

(1A2,2C9,

2C19)

3.37

ZINC000000346674

-8.4

1080

High

Yes

CYP

(1A2,3A4)

3.25

ZINC000000000903

-8.8

1080

High

Yes

CYP

(1A2)

3.33

ZINC000039247014

-8.8

1080

High

Yes

CYP

(1A2,2C9,3A4)

3.43

ZINC000010152022

-8.2

1080

High

Yes

CYP

(1A2,

2C19)

3.24

ZINC000000347721

-8.8

1080

High

Yes

CYP

(1A2,2C9)

3.46

ZINC000079424448

-8.2

1000

High

Yes

CYP

(1A2,3A4)

3.33

ZINC000000702142

-8.3

1000

High

Yes

CYP

(3A4)

3.61

ZINC000039247035

-8.5

1000

High

Yes

CYP

(1A2,3A4)

3.31

Page 8 of 18

F1000Research 2023, 12:1332 Last updated: 12 MAR 2024

Table

Zolpidem

analysis

data.

compound

Docking

scores

(mg/kg)

Blood

brain

barrier

permeability

P-glycoprotein

substrate

Gastrointestinal

absorption

Metabolsm

Lipinski

violations

Synthetic

accessibility

Zolpidem

-8.1

695

yes

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

2.93

ZINC000000003876

-8.7

1000

Yes

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

2.93

ZINC000067665462

-8.1

1000

Yes

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

2.92

ZINC000065743121

-8.3

1000

Yes

High

CYP

(1A2,2C9,

2C19,3A4)

2.9

ZINC000041288365

-8.7

1000

Yes

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

2.71

ZINC000013801078

-8.9

1000

Yes

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

2.78

ZINC000041292591

-8.9

695

Yes

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

2.78

ZINC000022054496

-8.1

1190

Yes

High

CYP

(1A2,2C9,

2C19,3A4)

2.62

ZINC000071853335

-8.0

695

Yes

High

CYP

(1A2,,

2C19

2D6,)

2.46

ZINC000041282761

-8.0

695

Yes

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

2.45

ZINC000063832471

-8.6

695

Yes

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

2.75

ZINC000064675847

-8.6

695

Yes

High

CYP

(1A2,2C9,

2C19

2D6,3A4)

2.85

ZINC000426519011

-8.8

695

Yes

High

CYP

(1A2,

2C19

2D6,3A4)

2.5

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F1000Research 2023, 12:1332 Last updated: 12 MAR 2024

Results and discussion

Suvorexant and its analogues

Suvorexant interacts with the orexin receptor through van der Waal forces hydrogen bonds, carbon-sulfur, Pi-sulfur, Pi-Pi
alkyl, alkyl, and Pi alkyl (

Figure 1

). The increase in interaction forces between the receptor and the drug molecule

increases the duration of activity of the drug in the receptor hence the activity of the drug and decreasing the concentration
of the drugs needed to provide therapeutic effects.

Docking scores, pharmacokinetic and toxicity profiles of 20 compounds similar to suvorexant were analyzed.
From the 20 molecules, 12 compounds (

Table 1

) showed better docking scores compared to the parent drug. All the

molecules showed higher Gastrointestinal absorption indicating that the molecules can easily be administered orally.

The parent molecule had a poor penetration to the central nervous system (CNS) which is their site of action. five
molecules showed higher CNS bioavailability as compared to the parent compound. They include ZINC000206774725,
ZINC000206774070, ZINC000206774330, ZINC000206774469 and ZINC000253409181.

Suvorexant

ZINC000206774070 and ZINC000206774469 have good CNS penetration ability but those molecules are good sub-
strates of P-glycoprotein. P-glycoprotein is a transporter that decreases the absorption of a drug by pumping the molecule
back into the lumen. As a substrate of P-glycoprotein, the drug concentration may not be enough to cause the desired
therapeutic effects.

All the molecules do not have any Lipinski violation. A molecule that violates Lipinski

’

s rule of five indicates its limited

bioavailability and oral absorption, these substances may need to be administered

via

other methods. In drug develop-

ment, the rule is often applied.

ZINC000206774725, ZINC000206774330, and ZINC000253409181 are not a substrate of P-glycoprotein (

Table 3

These molecules on the other hand have a greater Cytochrome P450 (CYP) enzyme interaction compared to the parent
molecule. They all interact with CYP 1A2,2C9, 2C19 2D6,3A4 as an inhibitor. These enzymes are essential in the
metabolism of many drugs.

Inhibition of those molecules may cause a serious interaction with other drugs which are

administered to the patient. The molecules can all be synthesized. They all have a synthesizability index of above 3.2.

LD50 was used in the estimation of the molecule

’

s toxicity profile. This is a dose that is necessary to kill 50%

of the population or test subjects. As a result, a higher LD50 value implies that a drug is less dangerous since a larger
dose is required to kill half of the population or test subjects.

ZINC000206774725, ZINC000206774330, and

ZINC000253409181 have a higher LD50 compared to the parent compound; suvorexant indicating that the molecules
are safer compared to the parent molecule.

Figure 1.

Suvorexant interaction with and orexin receptor.

Page 10 of 18

F1000Research 2023, 12:1332 Last updated: 12 MAR 2024

Triazolam and its analogues

Triazolam interacts with the GABA A receptor through van der Waals forces (

Figure 3

). These are forces that attract

neutral molecules to one another in gases solids and liquids. The binding may be weaker than that of other forms of
interactions, such as hydrogen bonding or electrostatic interactions. This may reduce the drug

’

s potency and at the same

time increase the drug selectivity.

Triazolam had a docking score of -8.1 (

Table 3

). Nine molecules had a better docking score compared to triazolam. Of the

nine molecules, only one molecule, ZINC000000702142, has poor penetration to the CNS this indicates that the molecule
may not be able to reach the site of action. All the molecules have good oral bioavailability. All the molecules are
substrates of the P-glycoprotein. This indicated that the molecules have less bioavailability.

Triazolam

ZINC000000000903, ZINC000010152022, and ZINC000000347721 do not interact with the CYP 3A4. The
CYP3A4 enzyme is involved in the metabolism of the majority of drugs

including Statins, Calcium channel

blockers, Benzodiazepines, Macrolide Antibiotics, Antidepressants, Antipsychotics, Immunosuppressants, and Opioids.
This makes it a potential for interaction with any drugs hence the need to be careful during co-administration.
ZINC000000000903 interacts with only one enzyme CYP 1A2. This molecule has then very few interactions as
compared to the other molecules.

These molecules studies have a higher LD50; ZINC000000000903(1080 mg/kg),

ZINC000010152022(1080 mg/kg), ZINC000000347721(1080 mg/kg) compared to triazolam (695 mg/kg) (

Table 3

Zolpidem and its analogs

Zolpidem interacts with the GABA A receptor through hydrogen bonds and van der Waal forces (

Figure 4

). This provides

a stronger receptor drug-receptor complex as compared to triazolam. interactions with, arginine, serine, methionine, and
leucine at positions 5 1, and 3, and two interactions between proline and arginine at locations 49 and 50 and 6 and
7 respectively.

Zolpidem has a docking score of -8.0. 10 molecules had a better docking score compared to the parent molecule
(

Table 4

). Of the 10 molecules ZINC000041288365 and ZINC000426519011 are substrates of P-glycoprotein trans-

porters indicating that the rest of the molecules have a good oral bioavailability. ZINC000065743121 and
ZINC000022054496 have very little interaction with CYP 2D6 molecule but interact with CYP 1A2,2C9, 2C19, and
3A4. The rest of the molecules interact with CYP 1A2,2C9, 2C19 2D6, and 3A4 as inhibitors. This increases the range of
drugs the molecules can interact with during the administration.

Figure 3.

Triazolam receptor interaction and GABA A receptor.

Page 12 of 18

F1000Research 2023, 12:1332 Last updated: 12 MAR 2024

Protein Receptors of the parent drugs compounds and their analogues were obtained from the

Protein data bank

Toxicity profile of the parent compounds and their structural analogues were obtained from the

Protox

server

Underlying data

Figshare: Developing potential drugs for

insomnia

through computational analysis:

23674614

This project contains the following underlying data

- Pharmacokinetisc of Ramelteon and its analogues.csv

- Canonical smiles of results for Suvorexant analogues.csv

- Pharmacokinetisc of Suvorexant and its analogues.csv

- Cannonical smiles of triazolam analogues.csv

- Pharmacokinetisc of Triazolam and its analogues.csv

- Pharmacokinetisc of Zolpidem and its analogues.csv

- Canonical Smiles for Zolpidem analogues.csv

Extended data

Figshare: Developing potential drugs for

insomnia

through computational analysis:

https://doi.org/10.6084/m9.figshare.

23674614

- Figures.docx

- Results Summary.docx

- Pharmacokinetic Properties.docx

- Docking Scores.docx

- Toxicity Profiles.docx

Data are available under the terms of the

Creative Commons Attribution 4.0 International license

(CC-BY 4.0).

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