1. Computer-aided Drug Design
Ligand Structure
database
(In silico)
Course: Drug Design
Course code:
Dr. Balakumar Chandrasekaran
Dr. Bilal Al-Jaidi
Assistant Professors,
Faculty of Pharmacy,
Philadelphia University-Jordan

2. Learning Outcomes At the end of this lesson students will be able to
Outline the entire process involved in the computer-aided
drug design methodologies.
Describe about molecular mechanics and quantum
mechanics.
Explain structure-based drug design including
the molecular docking technique.
Describe about QSAR and pharmacophore modeling
in ligand-based drug design.
Explain the steric-electronic modifications in de novo
drug design method.

3. Drug acting on different targets
Medicine or substance which has a physiological effect when administered into the body.
Drug acting on different targets
• Enzyme - inhibitors
• Receptor - agonists or antagonists
• Ion channels - blockers
• Transporter - update inhibitors
• DNA – blockers.

4. Molecular Modeling Techniques Quantum Mechanics Molecular Mechanics
Molecular Dynamics
Pharmacophore
Development
Hits from
Database Searches
Prioritization of Hits

5. Molecular Modeling: Computer Aided Drug Design
Molecular Mechanics
Quantum Mechanics
Structure-based Drug Design or
Target-based Drug Design
(Docking Studies)
Ligand-based Drug Design
QSAR Studies (2D, 3D etc.)
Pharmacophore Mapping
Three-dimensional (3D) Structure of Target Known (Receptor/enzyme)
Three-dimensional (3D) Structure of Target NOT Known/available
Homology Modeling of Target protein / receptor
Specify the binding site surrounding the bound co-crystal ligand
Search / Identify binding site in Homology Model
Specify the binding-site
Docking studies

6. Molecular Mechanics
It is the more popular method used to obtain molecular models as
it is simpler to use and
requires considerably less computing time to produce a model.
It assumes that the total POTENTIAL ENERGY (ETotal) of a molecule is given by the sum of all the energies of the attractive and repulsive forces between the atoms in the structure.
These energies are calculated using a Mechanical Model in which
atoms are represented by balls whose mass is proportional to their relative atomic masses
atoms are joined by mechanical springs corresponding to the covalent bonds in the structure.

7. ETotal = ∑EStretching + ∑EBend + ∑ETorsion + ∑EvdW + ∑EColumbic
Molecular Mechanics
Molecular mechanical calculations are normally based on
isolated structures at 0 K and
do not take into account the effect of the environment on the structure.
Using this model, ETotal may be expressed mathematically by equations, known as Force Fields
ETotal = ∑EStretching + ∑EBend + ∑ETorsion + ∑EvdW + ∑EColumbic

8. Quantum Mechanics H ѱ = E ѱ
It does not require the use of parameters similar to those used in molecular mechanics.
It is based on the realisation that electrons and all material particles exhibit wave-like properties.
Mathematics of wave motions are applied to electrons, atomic and molecular structure.
The basis of these calculations is the Schrodinger wave equation:
H ѱ = E ѱ
ѱ = time dependent wave function, which defines the state (nature and properties) of a system.
E ѱ = represents the total potential and kinetic energy of all the particles (nuclei and electrons) in the structure
H = Hamiltonium operator acting on the wave function ѱ

9. Quantum Mechanics Applications: Quantum mechanics is useful
for calculating the values of ionisation potentials, electron affinities, heats of formation, dipole moments and other physical properties of atoms and molecules.
to calculate the relative probabilities of finding electrons (the electron density) in a structure. This makes it possible to determine the most likely points at which a structure will react with electrophiles and nucleophiles.
to assess the nature of the binding of a possible drug to a target site.

10. Molecular Mechanics Vs Quantum Mechanics
Quantum mechanical methods
deal with electrons in a system, and
the calculations are very MUCH time consuming.
B. Molecular mechanics (force-field methods) on the other hand
ignore the electronic motions and
calculates the energy of the system as a function of the nuclear position only.
the calculations are very LESS time consuming.
However, molecular mechanics cannot provide answers that rely on the electronic distribution of a molecule.

11. Drug Design Strategies Based on Molecular Mechanics
Target-Based
Target
Protein Known
Docking
Ligand-based
Target
Protein
Unknown
Pharmacophore
&
3D-QSAR Study
Lead
Ligands
Ligands
Ligand Structure
database
(In silico)

12. Structure-based Drug Design
The macromolecular target can be isolated and crystallized…then the structure will be determined using X-ray crystallography.
This structure will not give information about the binding site.
The co-crystal structure (structure of protein with the inhibitor inside) is better (WHY?):
Where is the active site?
The distance between inhibitor and binding site boundaries.
The possible bonds between inhibitor and binding site.

13. How to use co-crystal structure in drug design
First the inhibitor will be removed from the active site (in silico).
The enzyme structure will be minimized to get the lowest energy state.
Then lead compounds will be inserted (docked) into the active site to see how they fit.
Best fit compounds will be synthesized and tested for activity.

14. Structure-based (target-based) Drug Design Active site / binding site
It is used to design a new drug molecule based on the knowledge of the three-dimensional (3D) structure of the biological target.
Active site / binding site

15. MOLECULAR DOCKING
Docking is the identification of low energy conformation after binding of ligand molecule with biological target (receptor or enzyme).
The compound that binds perfectly to the active site of target and having minimum energy may considered as drug molecule.
The process of “docking” a ligand to a binding site of a target mimics the natural course of interaction of the ligand and its target (receptor or enzyme) via the lowest energy pathway.

16. WHY DOCKING?
Drug work by interacting with biological target (receptor/enzyme)
Docking helps to decide a candidate drug will interact appropriately with a target protein?
Examine binding model of known ligands to suggest modification.
Screen databases of 3D structure to find novel ligands.
Drug interaction with receptor can be as an agonist or an antagonist.

17. Target receptor/ enzyme
Types to Docking
Ligand-protein docking
Protein-protein interaction
Protein–DNA interaction
Approaches to Docking
Ligand
Target receptor/ enzyme
Rigid body docking
Rigid
Semi-flexible docking
Flexible
Flexible docking
Approaches to Docking
Rigid body docking: Both target (protein) and ligand are treated
as rigid bodies.
B. Semi-flexible docking: Only the ligand is considered as flexible
target (protein) is considered as rigid body
C. Flexible docking: Both ligand and protein are treated as flexible
molecules.

18. Scoring Functions
During the docking process, they serve as fitness functions in the optimization of the placement of the ligand. When the docking is completed, the scoring function is used to rank each ligand in the database.
Some common scoring functions are: 1. Force-field methods 2. Empirical free energy scoring functions 3. Knowledge-based potential of mean
force

19. Docking Softwares Free for Academics: DOCK AutoDOCK Surflex FRED eHits
Commercial:
GOLD/Glide/FlexX/Discovery studio-CDOCKER.

20. If you do not have the crystal structure of your target enzyme
Three options:
Use recombinant DNA technology to produce the
enzyme using bacterial cell.
Use the homologue of this enzyme from other
organism such as bacteria or parasite (homology
modeling/comparative modeling).
Use Ligand Based Drug Design.

21. Ligand-based Drug Design
Here the crystal structure of the target enzyme or receptor is not available.
But their ligands are well defined and characterized.
This method not involves molecular docking or
homology modeling methods.
This method works based on the concept of
‘similar chemical structures have similar chemical
activity’.

22. Ligand-based Drug Design
This method will
Begin with biologically active compounds.
Describe what chemistry those compounds have
in common.
Few new compounds that match this description.
Compounds that match the description will also be active.
Initial two steps involving the process called
‘model building’ while the final two steps are known as ‘database screening’.

23. Methods in Ligand-based Drug Design
Description type
Molecular Properties, ADME
Discrete properties
Model building/QSAR
Statistics used in discrete properties
Substructure matching
Discrete 2D substructures
2D fingerprints
‘Bitstring model’ of 2D structure
Shape-based screening
Overall molecular shape
Field-based QSAR
Molecular field (steric/electrostatic)
3D pharmacophores
Specific arrangement of chemical features
(H-bond donors, acceptors, ring aromatic, hydrophobic)

24. QSAR (Quantitative Structure-Activity Relationship)
QSAR is a mathematical relationship between a biological activity of a molecular system and its geometric and chemical characteristics.
A general formula for a quantitative structure-activity relationship
(QSAR) can be given by the following:
Activity = f (molecular or fragmental properties)
QSAR attempts to find consistent relationship between biological activity and molecular properties, so that these “rules” can be used to evaluate the activity of new compounds.

25. QSAR (Quantitative Structure-Activity Relationship)
QSAR is a statistical approach that attempts to relate physico-chemical properties of molecules to their biological activities.
Various descriptors like molecular weight, number of rotatable bonds, LogP etc. are commonly used in QSAR.
Example: Hydrophobicity Vs Biological Activity
Activity of drugs is often related to P e.g. binding of drugs to serum albumin
(straight line - limited range of log P)
Log (1/C)
Log P .
0.78
3.82
Log 1 C æ è ö ø =
mlogP +

26. 1000’s of Structure Properties for Correlation
Molecular Properties
1000’s of Structure Properties for Correlation
CHEMICAL PROPERTIES
pKa
Log P
Solubility
Stability etc..
MOLECULE STRUCTURE
INTRINSIC PROPERTIES
Molar Volume
Connectivity Indices
Charge Distribution
Molecular Weight
Polar surface Area....
BIOLOGICAL PROPERTIES
Activity
Toxicity
Biotransformation
Pharmacokinetics

27. Types of QSAR Results Atom based - QSAR Field-QSAR G-QSAR
Good (blue contour) and Bad (red contour) regions for – Hydrogen bond donors and Acceptors, Hydropobic, Negative groups, Positive groups, electron with drawing and donating groups
Field-QSAR
(green) and unfavourable (yellow) steric contours; favourable (blue) and unfavourable (red) electrostatic contours;favourable (plum) and unfavourable (cyan) hydrogen bond donor contours;favourable (red) and unfavourable (magenta) hydrogen bond acceptor contours;favourable (yellow) and unfavourable (magenta) hydrophobic contours
G-QSAR

28. Pharmacophore Modeling
A pharmacophore is the ensemble of
steric and electronic features that is
necessary to ensure the optimal
molecular interactions with a specific
biological target and to trigger
(or block) its biological response

29. Pharmacophoric Features
H bond Acceptor-Lipophilic
H bond Acceptor
H bond Donor
Hydrophobic-
Aliphatic
Hydrophobic-
Aromatic
Hydrophobic
Ring aromatic
Negatively Ionizable
Positively Ionizable
Negative Charge
Positive Charge

30. Pharmacophore H-bonding donor H bond Donor Ring aromatic Hydrophobic
H-bonding acceptor
H bond Acceptor
H-bonding acceptor
H bond Acceptor

31. GENERATION of a pharmacophore model

32. Applications of Pharmacophore Modeling

33. De-novo Drug Design
Involves the design of a novel drug structure based on a knowledge of the binding site alone.
In this approach, you must have good supply of enzyme.
Sometimes the bacterial version of enzyme will be used (obtained by recombinant DNA technology).
The major drawback of this, is the bacterial version is not identical to the human enzyme…. But it can be considered very similar.

34. Steric-electronic modification
Steric hindrance and electronic stabilization have been used to stabilize labile drugs.
Two bulky methyl groups sterically shield the carbonyl group from being attacked
by a nucleophile.
The amide group is electronically more stable than ester group.

35. Steric-electronic modification
An other example is isoxazolyl penicillins:
Isoxazole ring is a bulky group which makes oxacillin β-lactamase stable.
Also it is an electron withdrawing group which stabilize the compound towards acid degradation.

36. Metabolic blockers
Is groups or substituents that normally added to the drug structure to impair its metabolism…result in prolonged duration of action.
Stable towards oxidation at this site

37. Self-destruct drugs
They are stable drugs that under certain conditions will spontaneously degraded …
This degradation does not
depend on the activity of
metabolic enzymes.

38. Sleeping drugs
An inactive drug which is only converted to the active form by external stimuli such as light, heat,…
Example:
Anticancer porphyrin drugs… large compound that will pass through the leaky membrane into the tumor cells… then the site of tumor will be exposed to red-laser beam to activate the drug…form a reactive oxygen radicals that will attack DNA and membranes.

39. Sentry Drugs Examples:
An other drug is co-administered with the principal drug to guard or assist it.
Examples:
Clavulanic acid + Amoxicillin.
Kaletra (combination of Ritonavir and Lopinavir): Ritonavir is a potent CYP450 inhibitors as well as a good antiviral agent…prevent Lopinavir oxidation.
The combination of Carbidopa and Levodopa.

40. Recommended Books
The organic chemistry of drug design by Richard B. Silverman. Second edition, Elsevier, 2004.
An introduction to Medicinal Chemistry by Graham L. Patrick. Fourth edition, Oxford, 2009.