Computational Drug Discovery and Design

3.5 Virtual Screening
of Ligands
and Multiple Receptor
Structures

In this chapter, we will deal with two possible virtual screening

strategies. The first uses Fred [51] and the associated OpenEye

software (seeSubheading2) and considers both the ligand and the

receptor to be rigid. This significantly increases the speed of the

calculation, at the cost of precision. It is therefore usual to use

several starting conformations for each ligand to be evaluated.

The second strategy considers flexible ligand but rigid receptor,

and relies on AutoDockVina [46], in which case a single conforma-

tion of each ligand is included in the library. It should be noted that

Vina can, in principle, define some receptor’s side-chains as being

flexible, but this significantly increases the computation time and is

not appropriate to fully mimic the conformational adaptation of the

receptor to the ligand binding.

1. Preparation of files for docking.
   Download the chemical compounds library you are inter-
   ested in or use in-house preassembled libraries. Most of the
   online chemical structures libraries are freely accessible for
   downloading (e.g., ZINC database, [52] and most of the
   compounds should be commercially available. These files have
   often an .sdf or .mol2 extension. First of all, generate 3D
   coordinates for the molecules. If you are planning to use Auto-
   Dock Vina, split them into .pdbqt files via OpenBabel with
   added hydrogens, removed salts and charges corresponding to
   the protonation state at physiological pH. The following com-
   mands can be used:

obabel –isdf drugs.sdf –omol2 –O drugs.mol2 –r –h –p7.2 –-gen3d

obabel –imol2 drugs.mol2 –opdbqt –O drugs.pdbqt –m

Filter your molecules according to selected physicochemical

properties (e.g., Lipinski’s rule of five). The Screening Assistant

v.2 (http://sa2.sourceforge.net) can be used to remove known

reactive compounds (covalent binders), warheads (noncovalent

binders) and to eliminate PAINS (Pan-Assay Interference) com-

pounds [53]. Alternatively, you can use the programs from the

OpenEye software suite to enumerate tautomeric states for each

molecule, to filter them, calculate partial atomic charges and to

generate low-energy conformers:

tautomers -in drugs.sdf -out taut_drugs.sdf

filter -i taut_drugs.sdf -o filt_drugs.sdf –typecheck

fixpka -i filt_drugs.sdf -o fixpka_drugs.sdf

molcharge -method am1bccsym fixpka_drugs.sdf drugs.mol2

omega2 drugs.mol2 drugs.oeb.gz

Molecular Dynamics in Virtual Screening 161