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Molecular Modelling
Rikesh Lal Shrestha
M.Pharm, 2nd Semester
Kathmandu University
Introduction
• Molecular modelling is define as Theoretical methods
and computational techniques use to mimic the behavior...
Why medicinal chemist use models?
• To help with analysis and interpretation of
experimental data.
• To uncover new laws a...
Molecular Modelling Strategies
A. Direct Drug Designing
B. Indirect Drug Designing
Direct Drug Designing
• In this approac...
• Indirect drug design
• The indirect drug design approach involves
comparative analysis of structural features of
known a...
Molecular Modeling Methods
• Molecular modelling in drug design is performed by
the two most common methods :
– Molecular ...
a) Molecular Mechanics:
• Molecular mechanism is used for calculation of
energy of atoms, force on atoms and their resulti...
POTENTIAL ENERGY SURFACE (PES)
• It is define as a function of nuclear co-
ordination i.e. the variations in the potential...
Study of the Force Field
• Force field is the set of parameters use to
describe the total potential energy of the
molecule...
Total energy expression Valence term energy
Valence term
• Valence term are interactions within the springs. A spring wants to relax to
its original shape.
Cross term
• Cross term is due to coupling between 2 springs.
It is a correction to independent spring model.
Non-bonding Interaction
• Non-bonded term is interaction between two balls.
Study of Electrostatics
• It involves the study of interatction between various
dipoles.
• All atoms have partial charge e...
Quantum Mechanics:
• Quantum mechanics provides information about
both nuclear position and distribution.
• Based on study...
• The Schrodinger equation is simplified by
– Born-Oppenheimer approximation
– Hartee-Fock approximation
1) Born-Oppenheim...
2) Hartee-Fock approximation
• This is a variation calculation, meaning that the
approximate energies calculated are all e...
Molecular Modelling Steps
Lead molecule
• Lead molecule is molecule that has pharmacological
or biological activity likely to be therapeutically use...
Energy Minimization
• It is the systemic modification of the atomic coordinates of a
model resulting in a 3 dimensional ar...
Conformational Analysis
• Conformation Analysis generally means
structure arrangement.
• Conformational analysis is need t...
• In this flow chart all
the bond length and
angle remain fixed
throughout the
calculation.
•This finally determine
the sp...
Limitation of Conformation analysis
• Each energy term has no absolute meaning only
the sum of energy term could be used.
...
Conformation Search
• Ligand flexibility is a matter of concern in
conformation search.
• As chemical structure is constan...
Conformation Search Strategy
• Increasing the rotation increment as much as possible.
• Freezing bonds that do not contrib...
Pharmacophore Modelling
• Pharmacophore is a group of atoms ( functional group)
common for active compound with respect to...
• Receptor map
Proposed for procaine
and cocaine
Receptor base Pharmacophore
modelling
• In this case, ligand molecules
are built up within the
constraints of the binding
...
Molecular Docking
• It is the process of predicting the protein-ligand complexes in which
the ligand molecules interact wi...
Steps in Ligand –Protein Docking
Key stages in Docking
Receptor selection and
preparation
• Building Receptor: The 3D
structure of receptor is
download fro...
DE Novo Ligand design
• If one fail to find a molecule with desire
interacting group by docking method, then
alternative i...
Linking
• The fragments, atoms, or
building blocks are either
placed at key interaction
sites.
• They are joined together
...
Molecular Dynamics
Method
• The building blocks are
initially randomly placed
and then by MD
simulation allowed to
rearran...
Quantitative Structure Activity Relationships
(QSAR)
• A QSAR should be:
– Explanatory ( For structures with activity data...
• The earliest example of QSAR were Hansch
analysis and Free-Wilson Analysis
• Free wilsion define a function that equates...
Conclusion
• Molecular modeling is an inexpensive, safe and
easy to use tool.
• Visualize the 3D shape of a molecule.
• Ca...
• Platinum based anticancer drugs have problem such as drug resistance and
systemic toxicity . So, research efforts to inv...
SYNTHESIS:
Fig: Synthesis route of trans-[Ru(Pir)2(CH3CN)2].
• Piroxicam is widely used oxicam which exhibits chemoprevent...
Conclusion of article :
• Trans-[Ru(Pir)2(CH3CN)2] Synthesis: The coordination of the piroxicam
anion to the Ru(II) ion ca...
Reference
1. Burger’s Medicinal Chemistry And Drug Discovery Vol 1;
Principles and Practice, 5th Edition
2. Drug design Me...
Molecular modelling
Molecular modelling
Molecular modelling
Molecular modelling
Molecular modelling
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Molecular modelling

Molecular modelling in medicinal chemistry

Molecular modelling

  1. 1. Molecular Modelling Rikesh Lal Shrestha M.Pharm, 2nd Semester Kathmandu University
  2. 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. 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. 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. 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. 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. 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. 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. 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. 10. Total energy expression Valence term energy
  11. 11. Valence term • Valence term are interactions within the springs. A spring wants to relax to its original shape.
  12. 12. Cross term • Cross term is due to coupling between 2 springs. It is a correction to independent spring model.
  13. 13. Non-bonding Interaction • Non-bonded term is interaction between two balls.
  14. 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. 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.
  16. 16. • 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) ()
  17. 17. 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.
  18. 18. Molecular Modelling Steps
  19. 19. 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.
  20. 20. 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.
  21. 21. 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.
  22. 22. • 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.
  23. 23. 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.
  24. 24. 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.
  25. 25. 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.
  26. 26. 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.
  27. 27. • Receptor map Proposed for procaine and cocaine
  28. 28. 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.
  29. 29. 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.
  30. 30. Steps in Ligand –Protein Docking
  31. 31. 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.
  32. 32. 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
  33. 33. 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.
  34. 34. 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.
  35. 35. 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.
  36. 36. • 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.
  37. 37. 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.
  38. 38. • 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.
  39. 39. 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].
  40. 40. 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.
  41. 41. 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.

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