dft

1. National Conference on Recent
Progress and Developments in
Pharmaceutical Sciences
DFT: Tools and
Protocols for Drug
Design
Rajesh K. Das
Department of Chemistry
University of North Bengal

2. Parameters
• Computer Aided Drug Design
• Introduction to molecular modeling
• Types of molecular modeling
• Quantum mechanics
o Ab- initio methods
o Semi-empirical methods
o DFT
• Applications
• References

3. Computer Aided DrugDesign
used to facilitate the design and discovery of new therapeutic
drugs.
 used at any of the following stages of drug discovery –
Hit identification using virtual screening.
QSAR

4. Objective ofCADD
• TO CHANGE FROM :
• Random screening against
disease assays.
• Natural products
• synthetic chemicals.
• CHANGE TO :
• Rational drug design and testing
• Speed up screening process
• Efficient screening
• De novo design
• Integration of testing into design
process

5. Introduction to molecular modeling
• Use of all sort of different strategies to
modes and to deduce information of a
system at the atomic level.
• It is possible to conclude that
computational chemistry is the
nucleus of molecular modeling.
• Because it includes the all
methodologies used in computational
chemistry like computation of the energy
of a molecular system, energy
minimization, Monte Carlo methods or
molecular dynamics.

6. Molecular ModelingStrategies
• Direct Drug Designing
• Designing of lead molecule.
• receptor site geometry is known;
• docking step with energy
minimization can be used to predict
binding strength.
• Indirect drug design
• receptor is unknown
• The indirect drug design is done from
the structure activity relation with a
hypothetical receptor site.

7. Quantum Mechanics
information about both nuclear position and
distribution.
Arrangement and interaction of electron and
nuclei of a molecular system.
nuclei are arranged in the space
 the corresponding electron are spread all over
the system in a continuous electronic density
 computed by solving the Schrodinger equation
Features

9. Quantum Mechanics
Applications
• For biomolecules this process can be done
within the Born- oppenheimer approximation
• the purposes of the Hartee-Fock self
consistent field is the appropriate procedure
to compute the electronic density and the
energy of the system

10. Types Of
Quantum
Mechanics
Ab-Initio
Methods
Hartree-Fock
Approximation
Density
Functional
Theory
Semi-
Imperical
Methods

11. Hartree-FockApproximation
• The central field approximation means columbic
electron-electron repulsion is taken into account.
• The energies are calculated in units called
Hartrees(1 Hartree= 27.2116 eV).
• Polyelectronic wave function for an atom as the
product of one-electron wave function.

12. Hartree-FockApproximation
•Advantages-
1. Small system
2. System requiring high
accuracy
• Disadvantages-
1. Computationally expensive
2. time consuming.

13. Semi-Empirical Method
• Semi-empirical quantum chemistry method is
based on the Hartree-Fock formalism, but make
many approximations.
• They are very important in computational chemistry
for treating large molecules where the full Hartree-
Fock method without the approximations is too
expensive.
.

14. Semi-Empirical Method
• Advantages-
 Semi-empirical calculations
are very fast compared to Ab
initio and even to Density
functional theory
 Medium sized
systems(hundreds of atoms)
• Disadvantages-
 Low accuracy

15. Density functionalTheory
• Advantages-
 Small system
 High accuracy
• Disadvantages-
 Difficulties to describe intermolecular
interactions, especially vander Waals
forces, charge transfer excitations;
transition states, global potential
energy surfaces and some other
strongly correlated system

16. STO : Slater Type Orbital
GTO: Gaussian Type Orbital
CGTO: Contracted Gaussian Type
Orbital BASIS SET: A basis set in theoretical
and computational chemistry is
a set of basis functions which are
combined in linear combinations to
create molecular orbitals
Basis Set
Basis
function
Polarisatio
n function
Diffuse
function

17. STO Basis Set Development: STO - nG
n= no. of Gaussian primitive function
used to represent one STO
STO-3G
STO-4G
STO-6G
STO-3G* (polarised version of STO-3G)
Pople Basis Set : X-YZg
X=no. of primitive Gaussian basis funcion
Y= linear combination of Y primitive
Gaussian function
Z= linear combination of Z primitive Gaussian
function

18. X-YZg
Double zeta basis set
X-YZWg
Triple zeta basis set
3-21G*-polarisation function on heavy atoms
3-21G** - polarisation function on heavy atoms + hydrogen
wave function
3-21+G - Diffuse function on heavy atoms
3-21++G - Diffuse function on heavy atoms + hydrogen wave
function
3-21+G* - Polarisation function on heavy atoms + hydrogen
wave function + diffuse function on heavy atoms

19. UHF = For open shell molecules, uses different MOs for the
different spinning of electrons.
RHF = For closed shell molecules, uses same MOs twice for the
different spinning of electrons.
B3LYP = The exact energy function is expressed in terms of Kohn-
Sham orbitals rather than the density. It is known as implicit
density functional.
One of the most commonly version is B3LYP (Becke, 3-parameter,
Lee-Yang-Peer.
RB3LYP: opposite spin in the open shell
UB3LYP: unpaired spin in the open shell
Restricted Unrestricted

21. Output Descriptors
HOMO
LUMO
Dipole Moment
Global Reactivity Descriptors:
Ionisation Potential (I)= EHOMO
Electron Affinity (A) = -ELUMO
Chemical Potential (µ) = (EHOMO+ELUMO)/2
Global hardness (ɳ) = (ELUMO-EHOMO)/2
Global softness (S) = 1/ɳ
Electronegativity (σ) = - µ
Electrophilicity index (ω) = µ2/2ɳ

23. Fig: Chemical Structure (A), optimized structure using DFT-RB3LYP 6-31(G) of HAM
A
B

24. Table 1: Calculated energy values (eV) of Hamamelitanin in
different solvents
using DFT-RB3LYP 6-31(G)
Compou
nd
EHOMO
(eV)
ELUMO
(eV)
EHOMO-1
(eV)
ELUMO+1
(eV)
ELUMO –
EHOMO
(eV)
ELUMO+1-
EHOMO-1
(eV)
Etotal (eV)
Gas -155.859 -34.207 -161.708 -21.176 121.652 140.532 -49696.25
Water -159.487 -32.282 -163.263 -25.619 127.205 137.644 -49695.38
DMSO -159.265 -31.394 -160.746 -23.323 127.871 137.423 -49695.68
CHN -159.117 -28.876 -160.153 -20.954 130.241 139.199 -49695.85
The chemical reactivity of the HAM in the various solvents follows the order:
Gas > Water > DMSO > Cyclohexane

25. Out of the 34 tested compounds 10 models have
the best docked as compared to the standard
drug hamamelitanin.

29. All compounds docked in the same domain of receptor

35. Higher no. of –COOH and –OH groups are
responsible for good binding affinity towards
M protease.

36. Remdesivir
HAM RA

42. Plants : Ocimum Sanctum (Tulsi), Zingiber Officinale
(Ginger), Justicial Adhatoda (Vasaka)

43. Docking of Ligand to the Active site of Receptor

44. Optimized Inhibitors
HOMO
LUMO
DM
ETOTAL
logP
MV
BBB
PPB
TPSA
Natoms
nON
nOHNH
nrotb
CMC
MDDR
WDI
Rule of five
Drug-
likeness
Drug Score
IC50
(µM)
Molecular
Docking
Optimized
Structure
(Using MD
simulation)
∆G binding
(kcal/mol)
Protein (PDB)
Inhibitors (binding db)
ADME
PreADMET
mol
inspiration
Osiris
Property
Explorer
Functionalisation
QM
Best potential Drugs
?

45. References
• Practical application of computer aided drug design, By Paul S.
Charifson, marcel dekker INC.
• Chapter 3, molecular modeling techniques, By Swami
Ramanand Teerth Marathwada University.
• Basis of molecular modeling and docking, slide share
• https://www.slideshare.net/ashwinimushunuri96/applications
-of-molecular-modeling
• https://www.slideshare.net/RikeshlalShrestha/molecular-
modelling-75429338

46. Acknowledgement
 Late Prof. Dr. Asim K. Bothra, Raiganj University to
motivate me to conduct research work in this field.
 High-Performance Computing (HPC) cluster of the
University of North Bengal for the computational
facility
 UGC, New Delhi for start- up grant

47. https://www.amazon.com/dp/1636481892
https://www.elivapress.com/en/book/book-
1539516993/