Computer-Assisted Drug Design (1)

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Computer-Assisted Drug Design (1)

1. Random Screening
2. Lead Development and Optimization using
   Multivariate Statistical Analyses.
3. Lead Generation Structure Based Drug Design
   using Computer Graphics and Computer Chemistry.

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Computer-Assisted Drug Design (2) Structure Based
Drug Design

• Computer Graphics
• Docking Study using Molecular Mechanics
• Lead Generation
• Generate Novel Compounds that
• Fit to the Pharmacophore Features
• ii) Optimize their Chemical Structures using
  Molecular Mechanics and Molecular Dynamics.

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Procedure of Structure Based Drug Design (Lead
Generation)

• Determine 3D structure of a target protein using
  X-ray crystallography and NMR (Nuclear Magnetic
  Resonance)
• Generate chemical structure that fits
• to the pharmacophore of the protein
• Using Computer Graphics, etc.
• Compute the interaction energy between the
  compound and the protein.
• Optimize the chemical structure in order to
  maximize the interaction energy

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Experimental Methods for Determining 3D
Structures of Proteins
1) X-ray crystallography more accurate than
NMR crystal has to be grown to a sufficient
size and volume 2) NMR information about
flexibility no need for crystals easy to
change conditions (pH, temperature, etc.)
size limit
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A Computational Method for Determining 3D
Structures of Proteins

• Homology Modeling using Sequence Homology
• Identify homologous proteins and determine the
  extent of their sequence similarity with one
  another and the unknown
• Align the sequences
• Identify structurally conserved and structurally
  variable regions
• Generate coordinates for core (structurally
  conserved) residues of the unknown structure from
  those of the known structure(s)
• Generate conformations for the loops
  (structurally variable) in the unknown structure
• Build the side-chain conformations
• Refine and evaluate the unknown structure.
• http//cl.sdsc.edu/hm.html

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Determination of Molecular Structure Using
Moolecular Mechanics
Etotal Estretch Ebend Etorsion EvdW
Edipole
minimize
EvdW
Etorsion
Ebend
Estretch
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Molecular Dynamics Calculation

• Determine the initial positions and the initial
  velocities of the atoms
• Compute Forces using the equation,
• According to the equation of motion,
• Fma,
• Compute the next position of the
• atoms

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Molecular Dynamics Calculation
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