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Virtual High throughput in silico screening

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					Tecniche vHTS per il Drug Design
Drug Discovery is:


                     Øinterdisciplinary
                     Øexpensive
                     Øtime-consuming
Drug Discovery is:

üDisease target identification
üDiscovery and optimization
 of lead structures
üClinical tests and approval




Survey of about 50 companies         Single new drug:
                                     $880 million
                                     15 years development

 75% efforts lost due to failures!
In silico Drug Discovery
ØBioinformatics: biological target identification and validation
ØCheminformatics: search for and optimization of chemical
 lead structures



   üCost saving: $130 million
   üTime saving: 0.8 years



Outline:
1. Cheminformatics: vHTS
2. Bioinformatics: Systemic approaches
Real vs. In Silico HTS




                         ØFlexibility
   In Silico vHTS        ØCost-effectiveness
                         ØSpeed
vHTS: modelling molecular recognition
       ØHighly sophisticated way to query databases

       ØStrongly simplified simulation of high-throughput
        screening essays



                          vHTS



Principle of similarity      Principle of complementarity
vHTS: principle of similarity (ligand based)

  If one or more active compounds are known




  Search databases for more potent molecules



  Three categories:
     ØAlignment / Superimposition
     ØPharmacophore modeling
     ØQuantitative structure-activity relationship (QSAR)
Ligand-based methods: Alignment

 Single 3D structure as a template




 Superpositioning and scoring of molecules from databases




 Scoring: steric and physicochemical properties
Ligand-based methods: Pharmacofores
A pharmacophore is the 3D arrangement of chemical groups
that is required for the biological activity of a molecule




1. Generated from a series of known active
   compounds
2. Database-search for molecules that fulfill the
Metodi Ligand Based: QSAR
QSAR methods are statistical approaches that correlate
biological data with molecular descriptors to derive QSAR
models.




QSAR models are then used to predict the activity of novel
compounds
vHTS: modelling molecular recognition
       ØHighly sophisticated way to query databases

       ØStrongly simplified simulation of high-throughput
        screening essays



                          vHTS



Principle of similarity      Principle of complementarity
Drug Design and Structural Genomics




        72717 structures (27 April 2011)
vHTS: principle of complementarity (receptor based)

  Knowledge of the receptor 3D structure allows…




   …screening for molecules that fit the active site


   Receptor Based Methods: Docking
Metodi Receptor Based: Docking
               3D Structure Determination

                  Site Representation

         Site Identification/Characterization

                   Ligand Generation

     Docking                                De Novo Design
                        Scoring

     DGbind = DGcomplex – (DGligand – DGreceptor)
          DGbind = -RT ln Keq = -RT ln Kd
Metodi Receptor Based: Docking
 Problem 1: PES sampling

ØReceptor flexibility:
   • Difficult to predict from X-ray data
   • Computationally unfeasible in HTS
ØLigand flexibility


 Problem 2: Scoring and rankings

ØComputational time limits (vHTS)
ØEmpirical forcefield

üConsensus scoring
            Our job: Sampling the PES of
                      molecules


 Energia di una molecola in
 funzione delle coordinate
 atomiche




• minimi: conformazioni
• punti sella: stati di transizione
             QM-based methods
• QM methods are based on the following principles:
• Nuclei and electrons are distinguished from each other.
• Electron-electron (usually averaged) and electron-nuclear
  interactions are explicit.
• Interactions are governed by nuclear and electron charges (i.e.
  potential energy) and electron motions.


Interactions determine
the spatial distribution
of nuclei and electrons
and their energies.
           MM-based methods
MM methods are based on the following principles:
Nuclei and electrons are lumped into atom-like particles.
Atom-like particles are spherical and have a net charge.
Interactions are based on springs and classical potentials.
Interactions must be preassigned to specific sets of atoms.


Interactions determine the
spatial distribution of
atom-like particles and
their energies.
ADMET
 Full power of in silico screening of large databases:
 Ø      Integration of virtual molecular recognition with…
 Ø      …filter algorithms for ADMET




                                      üAdsorption
                                      üDistribution
                                      üMetabolism
                                      üExcretion
                                      üToxicity
Conclusions: what really is vHTS?

               It is not:
               üthe recipe to discover a new drug
               üa single method
               üa stand-alone approach


                It is:
                üa tool to drive rational screening
                üthe integration of several methods
                üa key actor in drug discovery

				
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