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Pharmacophore generation for virtual screening

Olivier Taboureau

Computational Chemical Biology CBS-DTU

! Pharmacophore: main interest in drug discovery, definition, chemical features. ! Different aspect to take account (pH, conformation, alignment, binding site). ! Pharmacophore flexibility (example with hERG potassium channel). ! Automatic identification of pharmacophores.

Pharmacophore: main interest in drug discovery, definition, chemical features.

Chemoinformatics and drug design

! Chemoinformatics refers to the building and use of chemical databases and linked the information related to (like chemical and/or biological properties) for the identification or optimisation of new drugs.

An important part of drug design is the prediction of small molecules binding to a target protein. (docking can do that with small set of compounds)

A pharmacophore is a reasonable qualitative prediction of binding by specifying the spatial arrangement of a small number atoms of function groups. The prediction can be done on large databases.

Pharmacophore definition
A pharmacophore is the ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger (or to block) its biological response. A pharmacophore does not represent a real molecule or a real association of functional groups, but a purely abstract concept that accounts for the common molecular interaction capacities of a group of compounds towards their target structure.

Pharmacophore: chemical features

! The chemical features can be hydrogen bonds acceptors, hydrogen bond donors, charge interactions, hydrophobic areas, aromatic rings, positive or negative ionizable group.) The shape or volume is also considered.





Acc & Don

Start to be complex !!!

! Pharmacophores represent chemical functions, valid not only for the curretly bound, but also unknown molecules.

Example 1
Atom is acceptor if he can attract an hydrogen (nitrogen, oxygen or sulfur and not an amide nitrogen, aniline nitrogen and sulfonyl sulfur and nitro group nitrogen), and donor if he can give an hydrogen. Acceptor Acceptor Donor Aro ring center



Acc & Don Acc Acc & Don Acc & Don




Effect of pH

pH = 7 Donor

pH = 1

Example 2 with 3 inhibitors

Agonist at D2 receptor ! Dopamine (2 rotations and 2 OH groups)

! Apomorphine (no rotations)

! 5-OH DPAT (one OH group and many rotation)

Example 2
Active agonists define important groups:
! ! ! ! -Aromatic ring -meta OH group -N atom, right distance from aromatic ring -other molecular scaffolding does NOT show a consensus.

Different aspects to take account

Which conformation?
! Some drugs are rigid (e.g, strychnine, a Glycine receptor antagonist)

! But most drugs have some conformational flexibility, and can have different shapes (e.g, sildenafil)

Pharmacophore should be presented only by high energy conformation (Xray, NMR, minimisation, stochastic search)

With a group of compounds

! Alignment from models

! Can be messie!!!

! Alignment from Xray structures

! Can be messie too !!!

! Binding site activity is flexible too

Sometime problem with antagonists

! ! ! Antagonist active conformation may be different from agonist Extra binding site: umbrella effect Example with D2 receptor


Active site


Active site

Umbrella effect



Active site

Active site

Antagonists may bind at an additional site

Example with opioids
agonist antagonist

Antagonist binding site

Agonist binding site

Pharmacophore flexibility
A pharmacophore is usually obtained by connecting the average spatial positions of the pharmacophoric points of all the molecules. But sometime, several binding site. Therefore, several pharmacophores can be a solution.

Example with hERG channel blockers

Are features of the site unique to hERG?

Automatic pharmacophore identification

! As many protein structures are described as sets of points, pharmacophore identification is commonly reduced directly to the problem of finding common points to all functional ligand conformations.

Pharmacophore identification
!!From X-ray crystallography measure X-ray structure with drug at the active site (can sometime be done) or infer binding by measuring distance between likely binding groups. !!From comparison of active compounds The traditional way to identify binding groups. !!Automatic identification of pharmacophores (GALAHAD, Pharmacophore elucidation)

Automatic Pharmacophore Elucidation

Automatic pharmacophore elucidation

generate a collection of pharmacophore queries from a collection of compounds some or all of which are active against a particular biological target. !!Identify low-energy conformations !!Run through multi-objective GA !!From an optimized sets of conformers, a hypermolecular alignment in Cartesian space is done. !!Score models based on 3D geometric consistency

Automatic pharmacophore elucidation in MOE

It is based on pharmacophore alignment

Automatic pharmacophore elucidation in MOE

Automatic pharmacophore elucidation in MOE

Weakness ! 2D pharmacophore is faster but less accurate compared to 3D pharmacophore. ! Its based only on the structure and conformation. No interactions with the proteins is integrated. Its sensitive to physicochemical features.

Advantages ! Pharmacophore can be used for virtual screening on a large database ! ! It does not need to know the binding site It can be used for the design optimization of a drugs and for the design of new scaffolds. It can be run on 2D conformation

Time for a break