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Review
. 2012 Apr;17(7-8):310-24.
doi: 10.1016/j.drudis.2011.10.024. Epub 2011 Oct 26.

Classification of scaffold-hopping approaches

Hongmao Sun  1 , Gregory Tawa, Anders Wallqvist
Affiliations
Review

Classification of scaffold-hopping approaches

Hongmao Sun et al. Drug Discov Today. 2012 Apr.

Abstract

The general goal of drug discovery is to identify novel compounds that are active against a preselected biological target with acceptable pharmacological properties defined by marketed drugs. Scaffold hopping has been widely applied by medicinal chemists to discover equipotent compounds with novel backbones that have improved properties. In this article we classify scaffold hopping into four major categories, namely heterocycle replacements, ring opening or closure, peptidomimetics and topology-based hopping. We review the structural diversity of original and final scaffolds with respect to each category. We discuss the advantages and limitations of small, medium and large-step scaffold hopping. Finally, we summarize software that is frequently used to facilitate different kinds of scaffold-hopping methods.

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Figures

Figure 1
Figure 1
Structures of pain killing drugs (a) Morphine, (b) Tramadol, and (c) 3D superposition of (a) in green and (b) in magenta.
Figure 2
Figure 2
Structures of antihistamine drugs (a) Pheniramine, (b) Cyproheptadine, (c) Pizotifen, (d) Azatadine, (e) superposition of drugs (a) in magenta and (b) in green, and (f) superposition of drug (b) in green and (d) in magenta.
Figure 3
Figure 3
Structures of phosophodiesterase enzyme type 5 (PDE5) inhibitors (a) Sildenafil, (b) Vardenafil, and cyclooxygenase (COX-2) inhibitors (c) Rofecoxib and (d) Valdecoxib.
Figure 3
Figure 3
Structures of phosophodiesterase enzyme type 5 (PDE5) inhibitors (a) Sildenafil, (b) Vardenafil, and cyclooxygenase (COX-2) inhibitors (c) Rofecoxib and (d) Valdecoxib.
Figure 4
Figure 4
Structure of the Cannabinoid 1 (CB1) antagonist Rimonabant and its derivatives.
Figure 5
Figure 5
Structures of a triaryl bis-sulfone Cannabinoid 2 (CB2) receptor inhibitor (a) and its biaryl analog (b). The superposition of both structures (c) (molecule (a) in magenta and (b) in green) was calculated by using the Flexible Alignment program in MOE [21].
Figure 5
Figure 5
Structures of a triaryl bis-sulfone Cannabinoid 2 (CB2) receptor inhibitor (a) and its biaryl analog (b). The superposition of both structures (c) (molecule (a) in magenta and (b) in green) was calculated by using the Flexible Alignment program in MOE [21].
Figure 6
Figure 6
(a) Overlay of X-ray crystal structures of Cyclooxygenase 1 (COX-1) in magenta (PDB id: 3KK6) and COX-2 in cyan (PDB id: 3LN1) in complex with Celecoxib, and structures of diarylheterocyclic COX-2 selective inhibitors (b) DuP 697, (c) Celecoxib, and (d) Rofecoxib.
Figure 7
Figure 7
Prostaglandin EP1 receptor anatagonists. (a) biaryl amine series and (b) indole series. It is worth noting that reduction in entropy loss due to binding might be limited, since the intramolecular HBs of the parent compounds have already reduced molecular flexibility.
Figure 8
Figure 8
Structures of tyrosine kinase inhibitors. (a) Pyridopyrimidinone PD 166285 and (b) its urea derivative.
Figure 9
Figure 9
Structures of antiangiogenic agents. (a) Phthalazine PTK787/ZK222584, (b) its anthranilic amide analogue, and (c) Motesanib/AMG 706.
Figure 10
Figure 10
Structures of MAP (mitogen-activated protein) kinase-activated protein kinase 2 (MK2) inhibitors. (a) Pyrrolo-pyrimidone template, (b) amide analogue, (c) dihydroisoquinolinone derivative, and (d) the overlay of (a) in green and (b) in magenta.
Figure 10
Figure 10
Structures of MAP (mitogen-activated protein) kinase-activated protein kinase 2 (MK2) inhibitors. (a) Pyrrolo-pyrimidone template, (b) amide analogue, (c) dihydroisoquinolinone derivative, and (d) the overlay of (a) in green and (b) in magenta.
Figure 11
Figure 11
Structures of (a) Smac N-terminal tetrapeptide AVPI, (b) an oxazole derivative, (c) modified Smac tetrapeptide, and (d) an azabicyclooctane analogue.
Figure 11
Figure 11
Structures of (a) Smac N-terminal tetrapeptide AVPI, (b) an oxazole derivative, (c) modified Smac tetrapeptide, and (d) an azabicyclooctane analogue.
Figure 12
Figure 12
The structures of (a) Ang II (DRVYIHPF) and (b) benzodiazepine-based β–turn mimetic.
Figure 12
Figure 12
The structures of (a) Ang II (DRVYIHPF) and (b) benzodiazepine-based β–turn mimetic.
Figure 13
Figure 13
Structures of ZipA-FtsZ inhibitors. (a) Pyridyl-pyrimidine template from HTS and (b) ROCS-identified hit.
Figure 14
Figure 14
(a) Structure of BCL-xl inhibitor ABT-737, (b) the ligand binding site of BCL-xl illustrating the π– π stacking network formed between the ligand ABT-737(cyan) and the protein BCL-xl(green), and (c) the Cambridge Structural Database (CSD) query for reproduction of the π– π stacking.
Figure 14
Figure 14
(a) Structure of BCL-xl inhibitor ABT-737, (b) the ligand binding site of BCL-xl illustrating the π– π stacking network formed between the ligand ABT-737(cyan) and the protein BCL-xl(green), and (c) the Cambridge Structural Database (CSD) query for reproduction of the π– π stacking.
Figure 15
Figure 15
(a) The hit scaffold resulting from virtual screening of crystal structures in CSD and (b) the structure of the new BCL-xl inhibitor.
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