CZ3253: Computer Aided Drug design Lecture 4: Structural modeling of chemical molecules Prof. Chen Yu Zong Tel: 6874-6877 Email: [email protected] xin.cz3.nus.edu.sg Room 07-24, level 7, SOC1, National University of Singapore
Formula for chemical compounds:
Molecular formula:
Element(No. of atom) .Element (No. of atom) ….
Elements are placed in the order of C, N, H, O, and others. There can be exceptions to this rule.
         Examples:  
Carbon dioxide  CO2
Ammonia   NH3
Octane   C8H18
Formula for chemical compounds:
Condensed formula  
Formula reflects organization.
Members of the same functional group are placed together.
Example:
Formula for chemical compounds:
Structural formula
 
2D drawing of whole organization of chemical compound.
 
Example:
Formula for chemical compounds:
Chemical bonds:
 
There are 3 types of bonds:
single bond (1 bond between 2 atoms)
double bond (2 bonds between 2 atoms)
triple bond (3 bonds between 2 atoms)
Two atoms may be connected by one of these types of bonds according to their chemical properties.
The length of each types of bonds are in certain ranges
Chemical bonds:
Chemical bonds:
 
Problem solving example:
In each pair of bonds, predict which will be shorter? (a) C=C or C-C (b) C=C or C=O
Solution:
(a) C=C For the same pair of atoms, double bond is always shorter than single bond.
(b) C=O According to the Table, the length of C=O is 122pm which is shorter than that (134pm) of the C=C.
Chemical Compounds:
 
Stereochemistry
Three features:
Configuration (atom organization).
Conformation (atom spatial arrangement).
Shape (Surface landscape, steric packing)
Chemical Compounds:
 
Configuration:  
The organization of atoms and chemical bonds.  
Change of configuration requires breaking of bonds.
Chemical Compounds:
 
An important aspect of configuration is chirality.
Chirality defines the property of mirror image.  
If mirror image is not the same as the original, the compound is called chiral.
Chemical Compounds:
 
Example
Chemical Compounds:
 
Conformation:  
Determined by the spatial positions of its constituent atom.
Interconvertible without breaking and making of bonds.  
Conformation change is the key in many chemical reactions in living system.
Chemical Compounds:
III. Shape  
Steric packing (what part of space is covered by the compound).    
Surface features (cavities, grooves where other molecules can bind to).    
Molecular shape determines the binding of two molecules.
Atomic Motions in Chemical Compounds:
Atoms are not rigidly positioned.  
External and internal forces can induce atomic motions.
Some motions have chemical effect.
  Example:
Binding of a drug to a protein can induce an atomic motion in protein that leads to the change of the 3D shape of that protein.
This shape change makes a chemically important cavity inaccessible to other molecules.
Atomic Motions in Chemical Compounds:
The effect of motions are described by energy:    
Energy measures the ability to do work.  
Motion is associated with energy.  
There are two types of energy:
 
Kinetic energy — motional energy.
Kinetic energy is related to the speed and mass of a moving object. The higher the speed and the heavier the object is, the bigger work it can do.
Atomic Motions in Chemical Compounds:
Potential Energy — “positional” energy
Potential energy description:
Water falls from higher ground to lower ground. In physics such a phenomenon is modeled by potential energy description:
Objects move from higher potential energy place to lower potential energy place.
Atomic Motions in Chemical Compounds:
Potential Energy — “positional” energy
Potential energy description:
Water falls from higher ground to lower ground. In physics such a phenomenon is modeled by potential energy description:
Objects move from higher potential energy place to lower potential energy place.
Atomic Motions in Chemical Compounds:
Potential Energy — “positional” energy
Different types of bond motions are modeled by different energy functions.  
Energy terms are additive.  
The total energy determines overall effect.
Structural Modeling of Compounds: Basic Interactions and Their Models
Structural Modeling of Compounds: Basic Interactions and Their Models
Structural Modeling of Compounds: Basic Interactions and Their Models
Structural Modeling of Compounds: Basic Interactions and Their Models
Structural Modeling of Compounds: Basic Interactions and Their Models
Structural Modeling of Compounds: Basic Interactions and Their Models
Structural Modeling of Compounds: Basic Interactions and Their Models
Structural Modeling of Compounds: Basic Interactions and Their Models
Structural Modeling of Compounds: Basic Interactions and Their Models
Structural Modeling of Compounds: Basic Interactions and Their Models
Structural Modeling of Compounds: Basic Interactions and Their Models
Structural Modeling of Compounds: Basic Interactions and Their Models
Representation of Chemical Compounds
Molecular Descriptors
Constitutional
MW, N atoms,
Topological
Connectivity,Weiner index
Electrostatic
Polarity, polarizability, partial charges
Geometrical Descriptors
Length, width, Molecular volume
Quantum Chemical
HOMO and LUMO energies
Vibrational frequencies
Bond orders
Total energy
Molecular Descriptors
van der Waals volume
The sum of the non-overlaping volume of van der Waals sphere of each atom of the molecule
Molecular surface
The area of the surface contours generated by rolling a probing sphere against the surface atoms of the molecule
Molecular Descriptors
Molecular size vectors
Define ranges for distances and angles
Molecular Descriptors
Octanol-Water Partition
Coefficients
P = C(octanol) / C(water)
log P
like rG = – RT ln Keq
Hydrophobic – hydrophilic character
P increases then more hydrophobic
Molecular Descriptors
Molecular descriptors
Molecular descriptors
Molecular descriptors
Molecular descriptors
Topological pharmacophore fingreprint
Pharmacophore perception
Exceptions to simple rules
Effect of pH
Pharmacophore Construction
Pharmacophore Construction
Pharmacophore fingerprint