Tecniche vHTS per il Drug Design
Drug Discovery is:
 interdisciplinary
 expensive
 time-consuming
Drug Discovery is:
 Disease target identification
 Discovery and optimization
of lead structures
 Clinical tests and approval
Survey of about 50 companies
75% efforts lost due to failures!
Single new drug:
$880 million
15 years development
In silico Drug Discovery
 Bioinformatics: biological target identification and validation
 Cheminformatics: search for and optimization of chemical
lead structures
 Cost saving: $130 million
 Time saving: 0.8 years
Outline:
1. Cheminformatics: vHTS
2. Bioinformatics: Systemic approaches
Real vs. In Silico HTS
 Flexibility
In Silico vHTS
 Cost-effectiveness
 Speed
vHTS: modelling molecular recognition
 Highly sophisticated way to query databases
 Strongly 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:
Alignment / Superimposition
Pharmacophore modeling
Quantitative 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 specified
geometrical constraints
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
 Highly sophisticated way to query databases
 Strongly 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
 Receptor flexibility:
• Difficult to predict from X-ray data
• Computationally unfeasible in HTS
 Ligand flexibility
Problem 2: Scoring and rankings
 Computational time limits (vHTS)
 Empirical forcefield
 Consensus 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:

Integration of virtual molecular recognition with…

…filter algorithms for ADMET
 Adsorption
 Distribution
 Metabolism
 Excretion
 Toxicity
Conclusions: what really is vHTS?
It is not:
 the recipe to discover a new drug
 a single method
 a stand-alone approach
It is:
 a tool to drive rational screening
 the integration of several methods
 a key actor in drug discovery