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Rational approaches to improving selectivity in drug design.

Huggins DJ, Sherman W, Tidor B - J. Med. Chem. (2012)

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge, CB2 0XZ, United Kingdom. djh210@cam.ac.uk

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In this review we highlight some recent examples of successful come at a cost in optimal target affinity, with greater gains requiring greater cost... complexity and expense... Thus, considerable benefit can result from faster and less computationally demanding methods of identifying the same effects... for a number of other drug targets... However, drug targets exist in a complex environment and effect of cell trafficking on drug molecules, it is also possible and presented real-world examples of how these principles have been successfully applied in achieving selectivity... of drug molecules is an area that is now being explored and has recently the nature of molecular scaffolds and the promiscuity of molecules

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Shape complementarityin specific COX-2 inhibition. The crystalstructure of COX-2 complex from PDB entry 6COX(32) overlaidwith the apo crystal structure of COX-1 from PDB entry 3N8V.181 The ligand is displayed in atom colored space filling.The proteins are displayed as colored ribbons, and residues V523 fromCOX-2 and I523 from COX-1 are displayed as colored balls and sticks.The difference between the molecular surfaces of COX-2 residue V523and COX-1 residue I523 is displayed in magenta.
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fig2: Shape complementarityin specific COX-2 inhibition. The crystalstructure of COX-2 complex from PDB entry 6COX(32) overlaidwith the apo crystal structure of COX-1 from PDB entry 3N8V.181 The ligand is displayed in atom colored space filling.The proteins are displayed as colored ribbons, and residues V523 fromCOX-2 and I523 from COX-1 are displayed as colored balls and sticks.The difference between the molecular surfaces of COX-2 residue V523and COX-1 residue I523 is displayed in magenta.

Mentions: Shape complementarity betweenligands and receptors is a fundamental aspect of molecular recognition,29 and there are numerous cases where selectivityfor natural substrates is attributable to the specific shape of thebinding site.30,31 Unsurprisingly, molecular shapehas proven to be important in the rational design of selective inhibitors.For example, narrow selectivity is essential for effective COX-2 inhibitorsto control pain and inflammation while lowering the risk of pepticulcers and renal failure associated with nonselective COX inhibitors.Structural analysis by Kurumbail et al. highlighted a selectivitypocket that is accessible in COX-2 but not in COX-1 because of theV523I substitution.32 Other than this smallchange, the binding site residues are identical within 3.5 Åof the ligand in the COX-2 structure from PDB entry 6COX,32 and the only other changes in the binding site are Argto His and Ala to Ser in a flexible loop adjacent to the ligand. Overthe years, this V523I difference has been exploited to design inhibitorswith exquisite selectivity of over 13000-fold for COX-2 relative toCOX-1.33 The single extra methylene groupof Ile523 in COX-1 is enough to induce a significant clash with COX-2-specificligands, as seen in Figure 2. This exampleillustrates how small changes in protein shape can be used to gainsubstantial selectivity. However, it is important to note that otherwiseunfavorable interactions can be accommodated in some contexts becauseof molecular plasticity and the resulting rearrangement of the proteintarget. In the case presented above, COX-1 is not able to alleviatethe clash with the ligand through protein rearrangement. However,to predictively exploit this effect, accurate assessments of the potentialfor relieving unfavorable interactions must be made.


Rational approaches to improving selectivity in drug design.

Huggins DJ, Sherman W, Tidor B - J. Med. Chem. (2012)

Shape complementarityin specific COX-2 inhibition. The crystalstructure of COX-2 complex from PDB entry 6COX(32) overlaidwith the apo crystal structure of COX-1 from PDB entry 3N8V.181 The ligand is displayed in atom colored space filling.The proteins are displayed as colored ribbons, and residues V523 fromCOX-2 and I523 from COX-1 are displayed as colored balls and sticks.The difference between the molecular surfaces of COX-2 residue V523and COX-1 residue I523 is displayed in magenta.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3285144&req=5

fig2: Shape complementarityin specific COX-2 inhibition. The crystalstructure of COX-2 complex from PDB entry 6COX(32) overlaidwith the apo crystal structure of COX-1 from PDB entry 3N8V.181 The ligand is displayed in atom colored space filling.The proteins are displayed as colored ribbons, and residues V523 fromCOX-2 and I523 from COX-1 are displayed as colored balls and sticks.The difference between the molecular surfaces of COX-2 residue V523and COX-1 residue I523 is displayed in magenta.
Mentions: Shape complementarity betweenligands and receptors is a fundamental aspect of molecular recognition,29 and there are numerous cases where selectivityfor natural substrates is attributable to the specific shape of thebinding site.30,31 Unsurprisingly, molecular shapehas proven to be important in the rational design of selective inhibitors.For example, narrow selectivity is essential for effective COX-2 inhibitorsto control pain and inflammation while lowering the risk of pepticulcers and renal failure associated with nonselective COX inhibitors.Structural analysis by Kurumbail et al. highlighted a selectivitypocket that is accessible in COX-2 but not in COX-1 because of theV523I substitution.32 Other than this smallchange, the binding site residues are identical within 3.5 Åof the ligand in the COX-2 structure from PDB entry 6COX,32 and the only other changes in the binding site are Argto His and Ala to Ser in a flexible loop adjacent to the ligand. Overthe years, this V523I difference has been exploited to design inhibitorswith exquisite selectivity of over 13000-fold for COX-2 relative toCOX-1.33 The single extra methylene groupof Ile523 in COX-1 is enough to induce a significant clash with COX-2-specificligands, as seen in Figure 2. This exampleillustrates how small changes in protein shape can be used to gainsubstantial selectivity. However, it is important to note that otherwiseunfavorable interactions can be accommodated in some contexts becauseof molecular plasticity and the resulting rearrangement of the proteintarget. In the case presented above, COX-1 is not able to alleviatethe clash with the ligand through protein rearrangement. However,to predictively exploit this effect, accurate assessments of the potentialfor relieving unfavorable interactions must be made.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge, CB2 0XZ, United Kingdom. djh210@cam.ac.uk

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

In this review we highlight some recent examples of successful come at a cost in optimal target affinity, with greater gains requiring greater cost... complexity and expense... Thus, considerable benefit can result from faster and less computationally demanding methods of identifying the same effects... for a number of other drug targets... However, drug targets exist in a complex environment and effect of cell trafficking on drug molecules, it is also possible and presented real-world examples of how these principles have been successfully applied in achieving selectivity... of drug molecules is an area that is now being explored and has recently the nature of molecular scaffolds and the promiscuity of molecules

Show MeSH