drug design

1. A presentation on the topics of
Physicochemical, spectral, molecular docking and ADMET studies
of Paracetamol; A computational approach
Submitted by
MD. Ariful Islam
ID No: 16209017
Submitted to
Md. Moazzam Hossain
Lecturer
Dept. ACCE
Chittagong University
Course no: ACCE-509
Date of submission: 1st November, 2022

2. WHAT IS PARACETAMOL?
Generic Name: Paracetamol
Commonly called as: PCM
Alternate Name: Acetaminophan
Paracetamol (PCT) or acetaminophen is one of the most commonly used
analgesic and antipyretic drugs with relatively little anti-infammatory activity.
Paracetamol is commonly prescribed to relieve pain and fever.
Paracetamol treats following condition/s:
1. Fever
2. Pain
3. Osteoarthritis
4. Lower Back Pain
5. Headache
6. Toothache
7. Menstrual Period Pain
8. Cold/ Flu Pain

3. 1. Fever
It is widely prescribed to relieve fever in person of all ages.
Paracetamol isprescribed in children if temperature is
greater than 38. 5 Celsius or 101.3 Fahrenheit.
2. Pain
It is also prescribed to relieve mild to moderate pain.
3. Osteoarthritis
Some studies state that paracetamol is also used to treat
arthritis pain of knee,hand or hips.
4. Lower Back Pain
It is first line treatment of lower back pain
Fever
Pain

4. 5. Headache
Swiss, Austrian and German headache societies state
that Paracetamol with caffeine is also used in Headache.
In India paracetamol is also prescribed to relieve
headache.Paracetamol is also used to relieve migraine
in some countries.
6. Toothache
Some studies show that paracetamol is also used in
pain of tooth.
7. Menstrual Period Pain
Paracetamol is often prescribe with Dicyclomine
Hydrochloride or Mefenamic Acid to relieve pain
during menstrual period.
8. Cold/ Flu Pain
Paracetamol is also prescribed
Fig:Headache
Fig:Toothache

5. A computational approach
Methods and materials
Geometry optimization
Protein preparation, docking simulation, analysis and visualization
ADMET and Biological activities
Geometry optimization
Where is it used?
Experimental and theoretical investigations in the fields of
 chemical structure
 thermodynamics
chemical kinetics
Spectroscopy
others
Q:Why Geometry optimization is necessary?
to know the physical significance of the
obtained structure.

6. Geometry Calculation
Gap​(ΔE) = [εLUMO - εHOMO];
Hardness
η = [εLUMO - εHOMO]/2;
Softness
S =1/η;
Chemical potential
μ =[εLUMO + εHOMO]/2;
 Geometry Calculation is done
with the help of

7. Protein preparation, docking simulation, analysis and visualization
How is Protein preparation done?
By
1. erasing
water molecules
hetero atoms
inactive chain
2. adding
hydrogen atoms
Why is Molecular docking used?
To predict the predominant binding mode(s) of a ligand with a
target protein.

8. ADMET and Biological activites
Refers to
Chemical absorption
Distribution
Metabolism
Excretion
toxicity
AdmetSAR online server is used to predict the ADMET properties of
all drugs
PASS online server is utilized to predict the
biological properties

9. Software required for the Computitional Approach
1.Gaussian 09W 9.5 Revision D.01
2.GaussView 6.0.16 Win64
3.GaussSum-3.0.2-amd64
4.BIOVIA_2021.DS2021
5.Chimera-1.16
6.OriginPro 2016 SR0 b9.3.226
7.PyMoL22
8.SWISS-PDB

10. Which includes the following
Thermodynamic analysis
Molecular orbital analysis
Molecular electrostatic potential analysis
Molecular electrostatic potential analysis
Vibration frequency analysis
UV-Vis spectral analysis
Docking (Binding affinity) and non-bonding interaction analysis
ADMET analysis
Biological activities prediction
Results and discussion

11. Thermodynamic analysis
Free energy and enthalpy are related to
the absorption or release of energy
chemical stability of a molecule.
•The negative sign reveals the spontaneous binding and the high value alludes to
the more available bindings.
The dipole moment describes
electronic property.
Higher the dipole moment value higher the intermolecular interactions along
with more polar in nature.

12. Molecular orbital analysis
Fig: HOMO LUMO and band gap Fig: DOS plotting HOMO LUMO and Band Gap
HOMO–LUMO gap referes
chemical hardness
softness.
Larger HOMO–LUMO gap related to
high kinetic stability
low chemical reactivity.
Small HOMO–LUMO gap is important for low chemical stability

13. Molecular electrostatic potential analysis
Fig: Molecular electrostatic potential

14. Used
to parametrize force fields for classical molecular dynamics simulations
Mulliken and NBO methods have been utilized to compute the atomic partial
charges.
Atomic partial charge
FT-IR spectral analysis
to investigate any chemical structures which
confirm the presence of different functional groups
in the molecule
Show peak in range of 400-4000 cm-1
Vibration frequency analysis
Fig: FT-IR spectra of paracetamol

15. UV-Vis spectral analysis
Two characteristic electronic transition states is seen.
Kinetic stability and reactive sites depend on the first electronic
transition from the ground state (S0) to singlet (S1).
Paracetamol shows broad absorption bands at 266.85 nm along
with its oscillator strength 0.0083.
Fig: UV-Vis spectral analysis of paracetamol

16. Greater negative values of binding affinity indicate stronger binding between
drugs and the receptor protein.
Strong hydrogen bonding is the most significant contributing factor in
increasing binding affinity of drugs with the receptor.
Hydrogen bond of < 2.3 Å are able to increase the binding affinity.
The binding affinity of Paracetmol is − 6.2 kcal mol−1
Docking (Binding affinity) and non-bonding interaction analysis

17. Fig: Docked conformation of PCT at inhibition bounding site receptor protein 5F19 (Chain A)
Fig: Non-binding interaction of paracetamol

18. Figure:
(a) H-bond surface of 5F19 with paracetamol
(b) Charge surface of 5F19 with paracetamol
(c) Hydrophobicity surface of 5F19 with paracetamol
(d)Solvent accessibility(SAS) surface of 5F19 with paracetamol
(e) Ionizability surface of 5F19 with paracetamol

19. ADMET analysis
The structure shows positive response for blood brain barrier
(BBB) criteria
Predicting that drugs can pass through the BBB
PCT shows no inhibitory property for human

20. Biological activities prediction
The PASS prediction is used to predict more than 1000 biological and toxicological
studies
the prediction result is denoted by Pa (probability of compound being active) and Pi
(probability of compound being inactive)
Value Prediction
Pa > 0.7
likely show the experimental
activity
a known pharmaceutical agent
0.5 < Pa < 0.7
likely show the experimental
activity
unlike known pharmaceutical
agents
Pa < 0.5
unlikely to show the experimental
activity
Increasing the chance of new
compound

21. Properties Probability of compound
being active
Analgesic stimulant 0.793
Antiinflammatory 0.319
Methemoglobinemia 0.278
It is clear that these compounds have more antipyretic, anti-
inflammatory and analgesic activities

22. Computational tools are becoming popular in drug discovery and development to predict
unknown properties of new chemicals.
Conclusion
It can predicts the following without performing any costly experiment
Geometrical
thermodynamical
molecular orbital
Spectral
biological features