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Molecular Descriptors. C371 Fall 2004. INTRODUCTION. Molecular descriptors are numerical values that characterize properties of molecules Examples: Physicochemical properties (empirical) Values from algorithms, such as 2D fingerprints

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molecular descriptors

Molecular Descriptors

C371 Fall 2004

introduction
INTRODUCTION
  • Molecular descriptors are numerical values that characterize properties of molecules
  • Examples:
    • Physicochemical properties (empirical)
    • Values from algorithms, such as 2D fingerprints
  • Vary in complexity of encoded information and in compute time
descriptors for large data sets
Descriptors for Large Data Sets
  • Descriptors representing properties of complete molecules
    • Examples: LogP, Molar Refractivity
  • Descriptors calculated from 2D graphs
    • Examples: Topological Indexes, 2D fingerprints
  • Descriptors requiring 3D representations
      • Example: Pharmacophore descriptors
descriptors calculated from 2d structures
DESCRIPTORS CALCULATED FROM 2D STRUCTURES
  • Simple counts of features
    • Lipinski Rule of Five (H bonds, MW, etc.)
    • Number of ring systems
    • Number of rotatable bonds
  • Not likely to discriminate sufficiently when used alone
  • Combined with other descriptors for best effect
physicochemical properties
Physicochemical Properties
  • Hydrophobicity
    • LogP – the logarithm of the partition coefficient between n-octanol and water
  • ClogP (Leo and Hansch) – based on small set of values from a small set of simple molecules
    • BioByte: http://www.biobyte.com/
        • Daylight’s MedChem Help page
        • http://www.daylight.com/dayhtml/databases/medchem/medchem-help.html
        • Isolating carbon: one not doubly or triply bonded to a heteroatom
acd labs calculated properties
ACD Labs Calculated Properties
  • http://www.acdlabs.com
  • ACD Labs values now incorporated into the CAS Registry File for millions of compounds
  • I-Lab: http://ilab.acdlabs.com/
    • Name generation
    • NMR prediction
    • Physical property prediction
molar refractivity
Molar Refractivity
  • MR = n2 – 1 MW

-------- -----

n2 + 2 d

where n is the refractive index, d is density, and MW is molecular weight.

  • Measures the steric bulk of a molecule.
topological indexes
Topological Indexes
  • Single-valued descriptors calculated from the 2D graph of the molecule
  • Characterize structures according to size, degree of branching, and overall shape
  • Example: Wiener Index – counts the number of bonds between pairs of atoms and sums the distances between all pairs
topological indexes others
Topological Indexes: Others
  • Molecular Connectivity Indexes
    • Randić (et al.) branching index
      • Defines a “degree” of an atom as the number of adjacent non-hydrogen atoms
      • Bond connectivity value is the reciprocal of the square root of the product of the degree of the two atoms in the bond.
      • Branching index is the sum of the bond connectivities over all bonds in the molecule.
    • Chi indexes – introduces valence values to encode sigma, pi, and lone pair electrons
kappa shape indexes
Kappa Shape Indexes
  • Characterize aspects of molecular shape
    • Compare the molecule with the “extreme shapes” possible for that number of atoms
      • Range from linear molecules to completely connected graph
2d fingerprints
2D Fingerprints
  • Two types:
    • One based on a fragment dictionary
      • Each bit position corresponds to a specific substructure fragment
      • Fragments that occur infrequently may be more useful
    • Another based on hashed methods
      • Not dependent on a pre-defined dictionary
      • Any fragment can be encoded
  • Originally designed for substructure searching, not for molecular descriptors
atom pair descriptors
Atom-Pair Descriptors
  • Encode all pairs of atoms in a molecule
  • Include the length of the shortest bond-by-bond path between them
  • Elemental type plus the number of non-hydrogen atoms and the number of π-bonding electrons
bcut descriptors
BCUT Descriptors
  • Designed to encode atomic properties that govern intermolecular interactions
  • Used in diversity analysis
  • Encode atomic charge, atomic polarizability, and atomic hydrogen bonding ability
descriptors based on 3d representations
DESCRIPTORS BASED ON 3D REPRESENTATIONS
  • Require the generation of 3D conformations
    • Can be computationally time consuming with large data sets
    • Usually must take into account conformational flexibility
    • 3D fragment screens encode spatial relationships between atoms, ring centroids, and planes
pharmacophore keys other 3d descriptors
Pharmacophore Keys & Other 3D Descriptors
  • Based on atoms or substructures thought to be relevant for receptor binding
  • Typically include hydrogen bond donors and acceptors, charged centers, aromatic ring centers and hydrophobic centers
  • Others: 3D topographical indexes, geometric atom pairs, quantum mechanical calculations for HUMO and LUMO
data verification and manipulation
DATA VERIFICATION AND MANIPULATION
  • Data spread and distribution
    • Coefficient of variation (standard deviation divided by the mean)
  • Scaling (standardization): making sure that each descriptor has an equal chance of contributing to the overall analysis
  • Correlations
  • Reducing the dimensionality of a data set: Principal Components Analysis