A SEMINOR ONMOLECULAR MODELING IN DRUG DESIGN : A SEMINOR ONMOLECULAR MODELING IN DRUG DESIGN PRESENTED BY
Department of pharmaceutical chemistry.
LUQMAN COLLEGE OF PHARMACY, GULBARGA INTRODUCTION : INTRODUCTION Essential tool to the medicinal chemist in the drug design.
It is an scientific application for drug design that describes the generation and representation of 3D structure of molecules with associated physio-chemical properties.
Mol. Mod can combine computational chemistry and computer graphics
Mol. Mod techniques are derived from the concepts of Molecular orbitatals of Huckel, Mullikan and classical mechanical programs of Westtheimer, Wihery and Boyd.
Mol. Mod in Drug Design plays an IMP role in Drug Discovery process Molecular models allow us to “think like a molecule.” We see what a molecule sees & feel what a molecule feels. And these models provide a window on the molecular world. : Molecular models allow us to “think like a molecule.” We see what a molecule sees & feel what a molecule feels. And these models provide a window on the molecular world. Molecular Modeling methods : Molecular Modeling methods Molecular modeling in drug design is performed by the two most common computational methods.
Both these methods produce equations for the total energy (E) of the structure. MOLECULAR MECHANICS : MOLECULAR MECHANICS Molecular mechanics is used for calculation of energy of atoms, force on atoms and their resulting motion.
Molecular mechanics used to model the geometry of the molecule and motion of molecule
Used to get the global minimum energy structure Slide 6: Molecular Mechanics consider a
molecule as system of rigid balls
connected via springs depend strongly on concepts of bonding
neglect the electronic degrees of freedom
follows the Newtonian laws Methods used to study the molecular mechanics of molecules : Methods used to study the molecular mechanics of molecules Potential surface
Study of force field
Study of electrostatics
Conformational analysis POTENTIAL ENERGY SURFASE : POTENTIAL ENERGY SURFASE Potential energy surface is defined as a function of nuclear CO-ordinate i.e. The variations in the potential energies associated with geometry of the molecule.
The PES should not depends on the absolute location of the atoms, only on their location relative to one another.(i.e. the molecular geometry)
In order to reduce computational time an empirical fit to the potential energy surface is used. FORCE FIELD : FORCE FIELD Force field is a set of parameters used to describe the total potential energy of a molecule or system as a function of geometry. and this set of parameters is called “force field parameters”
The total energy is a 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. STUDY OF ELECTROSTATICS : STUDY OF ELECTROSTATICS It involves the study of interaction between various dipoles
All atoms have partial charge e.g. in C=O, C has partial positive charge, O atom has partial negative charge.
Two atoms that have the same charge repel one another.
In many cases molecules made of neutral group sand two adjacent atoms have opposite charges &behave like dipole.
Electrostatic energy falls off much less quickly than for vanderwaals interactions and may not be negligible even at 30A. MOLECULAR DYNAMICS : MOLECULAR DYNAMICS Molecular dynamics program allow the model to show the natural motion of atoms in the structure.
This is achieved by including the kinetic energy term of atoms in the force field equation by using equations based on Newton's law of motion.
In molecular dynamics the position of one atom changes with respect to the others.
The force on any particular atom can be calculated by,
F= m.a = -dv/dr = md2v/dt2 CONFORMATIONAL ANALYSIS : CONFORMATIONAL ANALYSIS It involves the determination or analysis of the spatial arrangement of the functional group of the respective molecule.
Following strategies used to study the conformational analysis
Rigid geometry approximation
Rigid body rotation
Conformational restriction strategies LIMITATIONS : LIMITATIONS Each energy term has no absolute meaning only the sum of energy terms could be used.
Force fields are best used within the class of compounds
Parameters in the force field are not transferable to others.
Properties related to the electronic structures (electrical conductivity, optical rotation, magnetic) are not accessible. QUANTUM MECHANICS : 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 motions applied to electrons, atomic and molecular structure. Slide 24: The calculations are based on
Schroedinger wave equation
Hψ (Rr) = Eψ(Rr)
H = Hamiltonian operator acting on the wave function ψ
Ψ = molecular wave function which define the nature and properties of a system
Eψ = total energy of the system i.e. the total potential and kinetic energy of all particles (nuclei and electrons) in the structure.
R = nuclear CO- ordinate
r = electronic CO-ordinate The above equation is simplified by1. Born – Oppenheimer approximation2. Hartee – fock approximation : The above equation is simplified by1. Born – Oppenheimer approximation2. Hartee – fock approximation Born – Oppenheimer approximation
it treats the electronic and nuclei motion separately
Nuclei is more heavy and static than electrons
The H broken into 2 terms i.e. kinetic energy(K) and potential energy(coulombic potential) (µ)
Hψ = Eψ
Hψ = (K+µ) ψ = Eψ
Hψ = (-1/2 V2 + 1/R) ψ = Eψ Example: H2 molecule. It have 4 particles i.e. 2 electrons(r1 & r2 position) and 2 protons(R1&R2 position)total energy of their interaction will be : Example: H2 molecule. It have 4 particles i.e. 2 electrons(r1 & r2 position) and 2 protons(R1&R2 position)total energy of their interaction will be H = -1/2 V12 -1/2 V22 +1/R1R2 –(1/r1R1-1/r1R2-1/r2R1-1/r2R2)+1/r1r2
1 2 3 4
1=K.E of electrons
2= coulombic interaction of electrons
4=electron- electron interaction ADVANTAGES : ADVANTAGES To calculate the value of potentials, electron affinities ,heat of formation, dipole moment and other physical properties
To find the electron density in a structure
To determine the points at which a structure will react with electrophiles sand nucleophiles
To determine the shape and electron density of a molecule Slide 28: Drug Design Structure based Ligand based MODELING ON KNOWN / UNKNOWN RECEPTOR SITES : MODELING ON KNOWN / UNKNOWN RECEPTOR SITES Drug design is generally divided in to two strategies. i.e.
Structure based/target based / receptor based drug design
Ligand based / analog based drug design Ligand (analog)
based drug design
Receptor structure is not known
Mechanism is known/ unknown
Ligands and their biological activities are known Target (structure) based drug design
Receptor structure is known
Mechanism is known
Ligands and their biological activities are known/ unknown PHARMACOPHORE MODELING : PHARMACOPHORE MODELING Pharmacophore: Group of atoms(functional group) common for active compounds w.r.t receptor and essential for its activity
the portion of the molecule containing the essential organic functional groups that directly interact with the receptor active site and, therefore, confers on the molecule the biological activity of interest
pharmacophores are used to define the essential features of one or more molecules with the same biological activity
a database of diverse chemical compounds can then be searched for more molecules which share the same features located a similar distance apart from each other ligands receptor interactions are typically polar positive, polar negative, or hydrophobic A 3D pharmacophore is developed in which the pharmacophore elements are arranged with respect to space : ligands receptor interactions are typically polar positive, polar negative, or hydrophobic 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 map is derived by looking at the pharmacophore groups and localized charges on the active ligands and hence assigning the active site Receptor Map Proposed for procaine and cocaine : Receptor Map Proposed for procaine and cocaine MOLECULAR DOCKING : MOLECULAR DOCKING Docking is the process of predicting the protein-ligand complexes in which the ligand molecules interact with the binding site of receptor. The ligand protein interactions are various types i.e. vanderwaals, electrostatic , hydrogen bonding etc Slide 36: Mechanism of drug binding: Ligand binding mechanism : Ligand binding mechanism DE novo ligand design : DE novo ligand design If one fails to find a molecule with the required interacting groups by database searching methods or docking , then the alternative is to construct a ligand having the active groups placed in a way that can interact with the interaction sites identified earlier.
This ligand construction process is called de novo ligand design.
Three categories of de novo ligand design are
Random connection BIBILOGRAPHY : BIBILOGRAPHY Molecular modeling, principles and application,
Andrew R leach, 2001
2) Practical application of computer aided drug design
Edpaul scharifson, 1997
3)Comprehensive medicinal chemistry vol. 4
Ed. Crown hansch
4)Introduction to molecular mechanics by
6)www.drugdesign.org Slide 44: THANK YOU