Medicinal Chemistry-III

Molecular Docking &
Pharmacophore Modelling

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Pharmacophore modelling
• Common features in a molecule:

• Hydrogen bond donors

• Hydrogen bond acceptors

• Aromatic rings

• Acidic groups

• Basic groups

• Positively charged centers

• Negatively charged centers

• Hydrophobic centers
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Pharmacophore modelling
• First definition of pharmacophore by Paul Ehrlich- a molecular framework that carrier
the essential features responsible for drugs biological activity

• Modified by Peter Gund- a set of structural features in a molecule that is recognized
at a receptor site and is responsible for that molecules biological activity

• Phe82 and Leu83 through two hydrogen bonds

• Hydrophobic region through cyclopentyl group

• Asp145 and Asn132 through hydrogen bonds

• In addition to distances that describe the 3D relationship among pharmacophore
points, angles, dihedrals, and exclusion volumes are also used
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3D Pharmacophore Modelling

Interactions between human cyclin-dependent kinase 2 and the adenine-derived
in the X-ray structure of the complex5 (PDB entry 1G5S).
inhibitor H717 as observedwww.DuloMix.com
3D Pharmacophore Modelling
• Structure based pharmacophore modelling

• Crystal structure of a target protein with its ligand bound to binding site can be used
to identify the 3D pharmacophore

• Protein-ligand structure can be loaded into the computer and complex is studied to
identify the bonding interactions which hold the ligand in binding site

• Done by measuring the distance between likely binding groups in drug with
complementary binding groups i.e., amino acids in binding site

• Positions can be mapped to generate the pharmacophore

• Database of compounds can be screened to identify the best matches
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Ligand based Pharmacophore Modelling
• If structure of target is unknown

• Can be identified based on the structures of a range of active compounds

• Molecules can be overlaid to ensure that important binding groups are matched up
as closely as possible

• All the chemical structures and IC50 values will be loaded to program

• It identifies the different important centers and their positions

• Program generates different set of conformations

• Adding all these together, gives a possible pharmacophore model

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4-hydroxyl piperidinol derivatives
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• Database of compounds can be
screened to identify the best
matches