Drug Discovery, Design, and Development - Molecular Docking Studies

What is docking?

The process of superimposing the 3-D structure of a potential drug on its possible target site

What are the two types of docking modelling programs?

Manual and automatic

What are the benefits of manual docking?

Fast, can be efficient if the user is familiar with the interacting site

What is a con of manual docking?

It is user dependent

What are the benefits of automatic docking?

It can be used to screen compound libraries for structures likely to bind to target binding site

What is a con of automatic docking?

While it is faster it is less accurate

What are the different methods of docking?

Rigid target/rigid ligand, rigid target/flexible ligand, flexible target/flexible ligand

Which type of docking is the simplest and quickest?

Rigid target/rigid ligand

Which type of docking is the most complex, expensive, and least practical?

Flexible target/flexible ligand

How are convex and concave regions found?

By finding the van der Waals surface accessible to a solvent molecule

How is the accessible surface found?

By rolling a sphere (water/solvent) over the van der Waals surface

What is a connolly surface?

The surface measured by the center of the rolling sphere in order to figure out the distance a docking molecule should be from the test molecule’s surface

What are dots of the connolly surface?

Regularly distributed points along the surface

What three parts of the molecule’s surface are included in a connolly surface?

A contact convex surface, a concave surface, and a saddle-shaped surface

What is the systemic matching operation?

Distance between ligand atoms is measured, distance between centers of pseudo atoms is measured, and ligands that match the distance of pseudo atoms are found

When is the docking procedure carried out?

After the matching operation is completed

What does the filtering process do?

Removes any solutions with steric clashes between unmatched ligand atoms and the binding site surface

What is the clique technique?

Hydrogen bonding groups are matched up on the ligand and binding site. Complementary H bonding groups must be correctly separated and have correct orientation.

What are interaction points?

Points in which all three steps of the clique technique are followed

What does the sphere surface represent in rigid docking H-bonding?

The optimum distance for H-bonding

What kind of dots is the sphere covered in when matching H-bonding groups?

Uniformly separated points that define the surface

How are points filtered in rigid docking H-bonding?

to only include points at the allowed bonding angle (alpha)

What are the filtered points used for in rigid docking H bonding?

Matching to ligand atoms

What does FLOG stand for?

Flexible ligands orientated on grid

What is FLOG?

A docking program that generates conformational libraries called flexibases which contain 10-20 conformations for each ligand studied

What is the problem with flexibase?

There is no guarantee that the active conformation will be included

What is the anchor and grow method?

Conformations are generated, ligand is fragmented, a rigid anchor is identified and docked, the ligand is reconstructed or grown