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Superimposition method- ligand based drug design


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superimposition or alignment methods used in the ligand based drug designing approach.classification of superimposition Rigid alignment method semiflexible alignment method and flexible method. application of superimposition method in pharmacoinformatics or bioinformatics

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Superimposition method- ligand based drug design

  2. 2. DEFINITION:- Superimposition is a method used in drug designing to establish a common alignment of 3D structures of investigated molecules.
  3. 3. REQUIREMENT FOR SUPERIMPOSITION  It is an important task in drug design to identify similarities of 3D structures of compounds that share similar biological activities, especially when the 3D structure of the macromolecular target molecule is not known.  Ideally, the ligands should bind to the same biological target within the same cavity of the molecule. Otherwise the deduced model will be misleading.  In order to reach this the 3D structures of the small ligand molecules are aligned to identify geometrical similarities and related spatial arrangements of chemical features.
  4. 4. Contd..  If this results in a plausible overlay it can be used for 3D-QSAR analyses to correlate the obtained conformations with the biological activity.  superimposition step is a crucial step for following analyses comprising e.g. i) pharmacophore evaluation ii) receptor modeling iii) ligand-based virtual screening iv) 3D-QSAR examination
  5. 5. Classification of superimposition or alignment method  Rigid alignment method  Semi-flexible alignment method  Flexible alignment method
  6. 6. Rigid alignment method  The approach for rigid-body alignment tries to maximize similarity of surface descriptors, generally given through Gaussian functions, approximating different properties, such as van der Waals overlap, electron density overlap. In this technique , we directly try to overlap one molecule over the other without any conformational or substituent change.
  7. 7. Semi-flexible alignment method  To allow the screening of different conformations for one molecule some approaches apply conformation generation methods.  In this method, they compare sets of precomputed conformations for one molecule in advance and afterwards perform a rigid body alignment of the generated conformations. Hence the name semi-flexible analysis.
  8. 8. Flexible alignment method  A method is presented for flexibly aligning small molecules. The method accepts a collection of small molecules with 3D coordinates as input and computes a collection of alignments. Each alignment is given a score, which quantifies the quality of the alignment both in terms of internal strain and overlap of molecular features.  RMSD(Root Mean Square Deviation) of atomic positions is the measure of the average distance between the atoms of superimposed molecules.  RMSD is used for estimation of divergence of the two aligned molecules.
  9. 9. Application of superimposition method  Superimposition method is employed in 3D QSAR studies in which CoMFA (comparative molecular field analysis ) describing 3D structure activity relationships in a quantitative manner is used.  In this method, set of molecules is first selected which will be included in the analysis. A certain subgroup of molecules is selected which constitutes a training set to derive the CoMFA model. The residual molecules are considered to be a test set which independently proves the validity of the derived models .  A pharmacophore hypothesis is derived to orient the superposition of all individual molecules and to afford a rational and consistent alignment.  Estimation of the energy values which the probe would experience in the corresponding position of the regular 3D lattice .
  10. 10. References  Sen, Sandip, N. A. Farooqui, T. S. Easwari, and Bishwabara Roy. "CoMFA-3D QSAR approach in drug design." (2012).32-36  R. D. Cramer III, D. E. Patterson, and J. D. Bunce, "Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins", J. Am.Chem. Soc.1988, 110, 5959-5967.  C. Lemmen and T. Lengauer, "Computational methods for the structural alignment of molecules", J. Comput. Aided Mol. Des. 2000, 14, 215-232
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