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Molecular Descriptors

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

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  1. Molecular Descriptors C371 Fall 2004

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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.

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

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