Molecular modelling in medicinal chemistry

1. Molecular Modelling
Rikesh Lal Shrestha
M.Pharm, 2nd Semester
Kathmandu University

2. Introduction
• Molecular modelling is define as Theoretical methods
and computational techniques use to mimic the behavior
of molecules and molecular system.
• Molecular modelling helps the scientist to visualize
molecule, to discover new compounds for drugs.
• The common feature of molecular modelling technique
is the atomistic level description of the molecular
system.
• Goal : To develop a sufficient accurate model of the
system so that physical experiment is not necessary.

3. Why medicinal chemist use models?
• To help with analysis and interpretation of
experimental data.
• To uncover new laws and formulate new theories
• To help solve new problems and hint solutions
before doing experiments
• To help design new experiments
• To predicts properties and quantities that is
difficult or even impossible to observe
experimentally.

4. Molecular Modelling Strategies
A. Direct Drug Designing
B. Indirect Drug Designing
Direct Drug Designing
• In this approach, the three dimensional features of
the known receptor site are determined from X-ray
crystallography to design lead molecule.
• Here, receptor sit geometry is known; the problem is
to find a molecule that satisfies some geometry
constraints is also good chemical match.
• After finding good candidates according to these
criteria a docking step with energy minimization can
be used to predict binding strength.

5. • Indirect drug design
• The indirect drug design approach involves
comparative analysis of structural features of
known active and inactive molecules that are
complementary with a hypothetical receptor
site.
• If the site geometry is not known, as is often the
case, the designer must base the design on other
ligand molecules that bind well to the site of
receptor.

6. Molecular Modeling Methods
• Molecular modelling in drug design is performed by
the two most common methods :
– Molecular mechanics
– Quantum mechanics
Both these methods produce equations for the total energy
(E) of the structure.

7. a) Molecular Mechanics:
• Molecular mechanism is used for calculation of
energy of atoms, force on atoms and their resulting
motion.
• Molecular mechanism is used to model the
geometry of the molecule and motion of molecule.
• Used to get the global minimum energy structure.
• Methods use to study molecular mechanics of
molecules are:
– Potential surface
– Study of force field
– Study of electrostatics

8. POTENTIAL ENERGY SURFACE (PES)
• It is define as a function of nuclear co-
ordination i.e. the variations in the potential
energies associated with the geometry of the
molecule.
• PES should not depend upon absolute location
of atoms, only on their location relative to one
another. (i.e. the molecular geometry)
• In order to reduce computational time an
empirical fit the potential energy surface is used.

9. Study of the Force Field
• Force field is the set of parameters use to
describe the total potential energy of the
molecule or system as a function of geometry.
• The total energy is the sum of Taylor series
expansions for stretches for every pair of
bonded atoms, and adds additional potential
energy terms coming from bending, torsional
energy, vanderwall energy, electrostatics and
cross terms.

10. Total energy expression Valence term energy

11. Valence term
• Valence term are interactions within the springs. A spring wants to relax to
its original shape.

12. Cross term
• Cross term is due to coupling between 2 springs.
It is a correction to independent spring model.

13. Non-bonding Interaction
• Non-bonded term is interaction between two balls.

14. Study of Electrostatics
• It involves the study of interatction between various
dipoles.
• All atoms have partial charge eg: in C=O, C has
partial positive charge, O atom has partial negative
charge.
• Two atoms that have same charge repel one another.
• In many cases molecules made of neutral group
sand two adjacent atoms have opposite charge and
behave like dipole.
• Electrostatic energy falls off much less quickly than
for vanderwaals interactions and may not be
negligible even at 30A.

15. Quantum Mechanics:
• Quantum mechanics provides information about
both nuclear position and distribution.
• Based on study of arrangement and interaction
of electrons and nuclei of a molecular system.
• It does not require the use of parameters similar
to those used in molecular mechanics.
• It is based on the wave properties of electrons
and all material particles.
• The mathematics of wave motion applied to
electrons, atomic and molecular structure.

17. • The Schrodinger equation is simplified by
– Born-Oppenheimer approximation
– Hartee-Fock approximation
1) Born-Oppenheimer approximation
– It treats the electronic and nuclei motion
sepatarely
– Nuclei is more heavy and static than electrons
– The H brolen into 2 terms i.e. Kinetic energy(k)
and Potential energy ( Coulombic potential) ()

18. 2) Hartee-Fock approximation
• This is a variation calculation, meaning that the
approximate energies calculated are all equal to or
greater than the exact energy.
• The energies are calculated in units called Hartees ( 1
hartee = 27.2116 eV)
• Hartee-Fock calculation start with an initial guess for
the orbital coefficients using a semiemperical method.
• This function is used to calculate an energy and a new
set of orbital coefficient.
• This procedure continues frequently until the energies
and orbital coefficient remains constant.

19. Molecular Modelling Steps

20. Lead molecule
• Lead molecule is molecule that has pharmacological
or biological activity likely to be therapeutically useful, but may
still have suboptimal structure that requires modification to fit
better to the target.
• Lead molecule is starting point for chemical modifications in
order to improve potency, selectivity,
or pharmacokinetic parameters.
• Furthermore, newly invented pharmacologically active moieties
may have poor druglikeness and may require chemical
modification to become drug-like enough to be tested
biologically or clinically.
• Natural materials are the sources of lead molecule. For
example: local anesthics from cocain, anticancer agent from
taxol.

21. Energy Minimization
• It is the systemic modification of the atomic coordinates of a
model resulting in a 3 dimensional arrangement of the atoms
in the model representing an energy minimum( a stable
molecular geometry to be found without crossing a
conformational energy barrier).
• Energy of molecule must be minimized so as find the most
stable structure of a molecule.
• The lead molecule makes several changes in its atom position
through rotation and calculates energy in every position. This
process is repeated many times to find the position with lowest
energy.
• The stable form of the molecule would be the one with the
lowest energy conformation.

22. Conformational Analysis
• Conformation Analysis generally means
structure arrangement.
• Conformational analysis is need to identify the
ideal conformation of a molecule.
• It is done by exploring the energy surface of
molecule and determining the conformation
with minimum energy.
• The biological activity of molecule is strongly
dependent on their conformation.

24. • In this flow chart all
the bond length and
angle remain fixed
throughout the
calculation.
•This finally determine
the spatial arrangement
of the functional group
of the respective
molecule.

25. Limitation of Conformation analysis
• Each energy term has no absolute meaning only
the sum of energy term could be used.
•Force field are best used within the class of
compounds.
•Parameters in the force field are not transferable to
others.
•Properties related to the electronic structure (
electrical conductivity, optical rotation, magnetic)
are not accessible.

26. Conformation Search
• Ligand flexibility is a matter of concern in
conformation search.
• As chemical structure is constantly changing
shape. The rotatable bond gives ligand
inherent flexibility.
• A ligand can adopt numerous conformations as
it attempts to bind within the active site.

27. Conformation Search Strategy
• Increasing the rotation increment as much as possible.
• Freezing bonds that do not contribute useful
information.(eg: methyl groups can be treated as united
atoms in many force fields).
• Separating bond rotation into two or more interacting
classes and sampling conformation separately for each
classes.
• Breaking molecule into pieces and sampling
conformation separately each piece. Eg: parent and
substituent moiety.
• Systemic energy sampling can be used to explore full
range of conformational space to find actual minima in
energy function.

28. Pharmacophore Modelling
• Pharmacophore is a group of atoms ( functional group)
common for active compound with respect to receptor and
essential for its activity.
• Hydrogen bond donors and acceptors, positively and
negatively charged group, and hydrophobic regions are the
typical feature.
• A 3D pharmacophore is developed in which the
pharmacophore elements are arranged with respect to space.
• Receptor Mapping : the volume of unknown receptor binding
cavity is derived by looking at the pharmacophore group and
localized charges on the active ligands and hence assigning the
active site.
• Pharmacophore modelling can be done by ligand based and
structure based.

29. • Receptor map
Proposed for procaine
and cocaine

30. Receptor base Pharmacophore
modelling
• In this case, ligand molecules
are built up within the
constraints of the binding
pocket by assembling small
pieces in a stepwise manner.
• These pieces can be either
individual atoms or molecular
fragments.
• The key advantage of such
method is that novel structures,
not contained in any database,
can be suggested.
Ligand based Pharmacophore
modelling
• The first category is about “
finding” ligand for a given
receptor, which is usually
referred to as database
searching.
• In this case, a large number of
potential ligand molecules are
screened to find those fitting the
binding pocket of the receptor.
• This method is usually referred
as ligand-based drug design.
• The key advantage of database
searching is that it saves
synthetic effort to obtain new
lead compounds.

32. Molecular Docking
• It is the process of predicting the protein-ligand complexes in which
the ligand molecules interact with the binding site of receptor. The
ligand protein interaction are various type i.e vanderwaals,
electrostatic, hydrogen bonding.
• Successful docking methods search high dimensional space
effectively and use a scoring function that correctly ranks candidate
docking.

33. Steps in Ligand –Protein Docking

34. Key stages in Docking
Receptor selection and
preparation
• Building Receptor: The 3D
structure of receptor is
download from PDB.
• This receptor must be
biologically active & stable.
• Identification of active site:
• The receptor can have many
active site but interested one
should be selected.
Ligand selection and
preparation
• Ligand can be selected from
PubChem, Chemsketch.
• Docking :
• The Ligand is docked onto
the receptor and the
interaction are checked.
• The scoring function
generates score, depending
on which the best fit ligand is
selected.

35. DE Novo Ligand design
• If one fail to find a molecule with desire
interacting group by docking method, then
alternative is to construct a ligand having the
active group placed in a way that can interact
with the interaction sites identified earlier.
• This ligand construction process is called de
novo ligand design
• Two categories of de novo ligand design are:
–Growing
–Linking

37. Linking
• The fragments, atoms, or
building blocks are either
placed at key interaction
sites.
• They are joined together
using pre-defined rules to
yield a complete molecule.
• Linking groups re
generated to satisfy all
required conditions.

38. Molecular Dynamics
Method
• The building blocks are
initially randomly placed
and then by MD
simulation allowed to
rearrange
• After each rearrangement
certain bonds were broken
and the process repeated.
• During this procedure high
scoring structures were
stored for later evaluation..
SCORING
• Each solution must be
tested to decide which is
the most promising.
This is k/a scoring
• Scoring function guide
the growth and
optimization of structure
by assigning fitness
values to samples space.
• Empirical scoring
function are a weighted
sum of individual
ligand-receptor
interaction.

39. Quantitative Structure Activity Relationships
(QSAR)
• A QSAR should be:
– Explanatory ( For structures with activity data)
– Predictive ( for structure without activity data)
• A QSAR can be used to explain or optimize:
– localized properties of molecules such as binding
properties.
– Whole molecule properties such as uptake and
distribution.
• QSAR must correlate general properties of
molecules with their biological activites.

40. • The earliest example of QSAR were Hansch
analysis and Free-Wilson Analysis
• Free wilsion define a function that equates
activity(define as Log of 1/ concentration) with
weighted descriptors, the weightings, or
coefficients, being determined by linear
regression. That is we have the equation:
– Log)1/c)= a1x1 + a2x2 + a3x3…..
Where C is the concentration required for activity,
x1,x2,x3, etc are the descriptor values(Usually 1 or 0
to represent absence or presence of features), and a1,
a2, a3 etc are the coefficients derived from linear
regression.

41. Conclusion
• Molecular modeling is an inexpensive, safe and
easy to use tool.
• Visualize the 3D shape of a molecule.
• Carry out complete analysis of all possible
conformations and their relative energies
• Predict the binding energy for docking a small
molecule i.e. a drug candidate, with a receptor or
enzyme target.
• Producing Block busting drug.
• Molecular modelling if used with caution, can
provide useful information to medicinal chemist
in medicinal research.

42. • Platinum based anticancer drugs have problem such as drug resistance and
systemic toxicity . So, research efforts to investigate drugs based on other
transition metals (ruthenium) with lower toxicity profiles.
• Among the different metal complexes generating interests, ruthenium complexes
are the best candidates, because several oxidation states are accessible for
ruthenium under physiological condition and its complexes can mimic iron in
binding to albumin and transferring with lower toxicity than that of platinum
therapies.
• Ruthenium based antitumor drugs are rapidly hydrolyzed in-vivo, forms potentially
active species and binds with biomolecules that strongly affect tumor activities.
• Also Ruthenium based anticancer drugs design are demanding because of
ruthenium ability to accumulate specifically in cancer tissues that provide
significant efficacy and lower toxicity.

43. SYNTHESIS:
Fig: Synthesis route of trans-[Ru(Pir)2(CH3CN)2].
• Piroxicam is widely used oxicam which exhibits chemopreventive and
chemosuppressive effects in colon, lung and breast cancer.
• Due to pharmacological applications of Ru(II) complexes, this article reports the
synthesis, spectral characterization, DNA and BSA binding and photocleavage properties
of a new mononuclear Ru(II) complex with piroxicam, trans-[Ru(Pir)2(CH3CN)2].

44. Conclusion of article :
• Trans-[Ru(Pir)2(CH3CN)2] Synthesis: The coordination of the piroxicam
anion to the Ru(II) ion can provide an enhanced activity of the drug because of
the synergism between the ligand and metal properties.
• Spectroscopic studies : this study shows that Pir‾ anion can intercalate into
DNA base pairs because of its extended  system while the Ru(II) complex
binds to DNA grooves.
• Photocleavage Properties : The photocleavage results of the plasmid pUC57
DNA show that the Ru(II) complex is more efficient DNA-photocleaver than the
Pir‾ anion.
• DNA binding study: The results suggested that Pir‾ anion binds to DNA in a
moderately via intercalation between the base stacks of double stranded DNA
while the Ru(II) complex is a groove binder and interacts with DNA with more
affinity.
• BSA binding study: Experimental results show that the secondary structure of
BSA molecules and the polarity of the microenvironment around the tyrosine
and tryptophan residues change in the presence of the Pir‾ anion and the Ru(II)
complex.
• Finally, the binding of the Ru(II) complex to BSA and DNA was modeled by
molecular docking and molecular dynamic simulation methods.

45. Reference
1. Burger’s Medicinal Chemistry And Drug Discovery Vol 1;
Principles and Practice, 5th Edition
2. Drug design Medicinal chemistry,Vol7, Ariens E.J
3. Foye’s Principle of medicinal chemistry, Sixth Edition
4. Introduction to molecular mechanics by Mahidol university
5. An introduction of medicinal chemistry, 4th edition, Graham.
L. Patrick
6. Cohen N.C. “guide book on molecular modelling on drug
design” Academic press limited publication, London.
7. Andrejus korolkovas ESSENTIALS OF MEDICINAL
CHEMISTRY, 2ND ED Friary,r. Jobs in the drug indrustry a
career guide for chemist; Academic Press: San Diego, CA,
2000.