Limits...
Strategic targeting of multiple water-mediated interactions: a concise and rational structure-based design approach to potent and selective MMP-13 inhibitors.

Fischer T, Riedl R - ChemMedChem (2013)

View Article: PubMed Central - PubMed

Affiliation: Institute for Chemistry and Biological Chemistry, Zurich University of Applied Sciences-ZHAW, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Water is an essential molecule in biological systems based on its role as the solvent for life. 1 Understanding the dynamics of the interaction between water and proteins represents a highly active field of research in molecular recognition, chemical biology, and drug discovery. 2, 3 In chemical biology, water‐mediated interactions offer tremendous opportunities for the development of novel chemical structures with biological activity, but due to its small size on the one hand and to its overwhelming abundance as a solvent on the other hand, water is often neglected when it comes to the detailed study of biological processes on a molecular or atomic level... Here, we report the very efficient use of X‐ray crystallographic data containing structural water molecules for the design and synthesis of potent and selective matrix metalloproteinase‐13 (MMP‐13) inhibitors by targeting multiple water‐mediated interactions between the protein target and the inhibitor... Analysis of the co‐crystal structure PDB 2OW910h (Figure 1) allowed us to design a novel scaffold of MMP‐13 inhibitors that was subsequently optimized with regard to its binding affinity by targeting water‐mediated interactions... Analyzing the close surroundings within 5 Å of the terminal phenyl groups of the designed phthalimide scaffold in the S1′ binding site of PDB 2OW9 with a resolution of 1.74 Å revealed several water molecules as attractive binding partners based on their distance from the inhibitor scaffold: water molecules HOH747, HOH813, HOH836, HOH915 on the right‐hand side and HOH794, HOH822, HOH890 on the left‐hand side (numbering based on protein chain A of PDB 2OW9; Figure 3)... Compared with their counterparts in PDB 2OZR, those water molecules are located at very similar positions and share the same binding motifs to the target protein: HOH747 binds to the backbone NH of Leu 164, HOH813 binds to the carboxylate side chain of Glu 202, and HOH836 binds to the catalytic zinc ion as well as to the backbone carbonyl of Pro 221... HOH915 on the other hand, which is also located in close proximity to the phthalimide scaffold, binds differently compared with its closest counterpart in PDB 2OZR (Figure 4)... On the left‐hand side, HOH794 and HOH822 in PDB 2OW9 bind in very similar positions compared with their counterparts in PDB 1XUD. 10a Again, those water molecules share the same binding motifs: HOH794 binds to the side chain carboxamide NH of Asn 194, and HOH822 binds to the backbone NH of Phe 231 as well as to the side chain amino functionality of Lys 119... HOH890 and its counterpart from PDB 1XUD do not show hydrogen bonding to the MMP‐13 target protein (Figure 5)... Compound represents a novel chemical scaffold with nanomolar inhibitory activity against MMP‐13, which was designed as a chemical scaffold that binds to the biological target by direct hydrogen bonds, as well as through a network of water‐mediated interactions (Figure 8)... In conclusion, we have demonstrated how to use co‐crystal structures of therapeutically relevant proteins very efficiently for the design of inhibitors by targeting multiple water‐mediated interactions with the target protein... By following this rational design concept of targeting multiple structural water molecules as binding partners for small organic molecules, we could enhance the binding affinity of our rationally designed phthalimide scaffold by a factor of 20... This led to a potent and selective nanomolar MMP‐13 inhibitor without any screening activities by a highly decreased number of synthesized compounds compared with classical medicinal chemistry or screening approaches and emphasizes the importance of structural water molecules for the design and discovery of novel small‐molecule inhibitors... We are currently expanding this structural design concept of targeting structural water molecules to other target proteins to show the broad applicability of this approach in the efficient design of novel molecules with tailored biological activity... Details of the synthetic protocols and characterization data for novel compounds can be found in the Supporting Information along with details of the biological methods used to evaluate these compounds.

Show MeSH
Interaction map of inhibitor 6: hydrogen‐bonding network to structural water molecules in addition to direct hydrogen bonding to Thr 224, Thr 226 and Met 232.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4281860&req=5

fig8: Interaction map of inhibitor 6: hydrogen‐bonding network to structural water molecules in addition to direct hydrogen bonding to Thr 224, Thr 226 and Met 232.

Mentions: Compound 6 represents a novel chemical scaffold with nanomolar inhibitory activity against MMP‐13, which was designed as a chemical scaffold that binds to the biological target by direct hydrogen bonds, as well as through a network of water‐mediated interactions (Figure 8).


Strategic targeting of multiple water-mediated interactions: a concise and rational structure-based design approach to potent and selective MMP-13 inhibitors.

Fischer T, Riedl R - ChemMedChem (2013)

Interaction map of inhibitor 6: hydrogen‐bonding network to structural water molecules in addition to direct hydrogen bonding to Thr 224, Thr 226 and Met 232.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4281860&req=5

fig8: Interaction map of inhibitor 6: hydrogen‐bonding network to structural water molecules in addition to direct hydrogen bonding to Thr 224, Thr 226 and Met 232.
Mentions: Compound 6 represents a novel chemical scaffold with nanomolar inhibitory activity against MMP‐13, which was designed as a chemical scaffold that binds to the biological target by direct hydrogen bonds, as well as through a network of water‐mediated interactions (Figure 8).

View Article: PubMed Central - PubMed

Affiliation: Institute for Chemistry and Biological Chemistry, Zurich University of Applied Sciences-ZHAW, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Water is an essential molecule in biological systems based on its role as the solvent for life. 1 Understanding the dynamics of the interaction between water and proteins represents a highly active field of research in molecular recognition, chemical biology, and drug discovery. 2, 3 In chemical biology, water‐mediated interactions offer tremendous opportunities for the development of novel chemical structures with biological activity, but due to its small size on the one hand and to its overwhelming abundance as a solvent on the other hand, water is often neglected when it comes to the detailed study of biological processes on a molecular or atomic level... Here, we report the very efficient use of X‐ray crystallographic data containing structural water molecules for the design and synthesis of potent and selective matrix metalloproteinase‐13 (MMP‐13) inhibitors by targeting multiple water‐mediated interactions between the protein target and the inhibitor... Analysis of the co‐crystal structure PDB 2OW910h (Figure 1) allowed us to design a novel scaffold of MMP‐13 inhibitors that was subsequently optimized with regard to its binding affinity by targeting water‐mediated interactions... Analyzing the close surroundings within 5 Å of the terminal phenyl groups of the designed phthalimide scaffold in the S1′ binding site of PDB 2OW9 with a resolution of 1.74 Å revealed several water molecules as attractive binding partners based on their distance from the inhibitor scaffold: water molecules HOH747, HOH813, HOH836, HOH915 on the right‐hand side and HOH794, HOH822, HOH890 on the left‐hand side (numbering based on protein chain A of PDB 2OW9; Figure 3)... Compared with their counterparts in PDB 2OZR, those water molecules are located at very similar positions and share the same binding motifs to the target protein: HOH747 binds to the backbone NH of Leu 164, HOH813 binds to the carboxylate side chain of Glu 202, and HOH836 binds to the catalytic zinc ion as well as to the backbone carbonyl of Pro 221... HOH915 on the other hand, which is also located in close proximity to the phthalimide scaffold, binds differently compared with its closest counterpart in PDB 2OZR (Figure 4)... On the left‐hand side, HOH794 and HOH822 in PDB 2OW9 bind in very similar positions compared with their counterparts in PDB 1XUD. 10a Again, those water molecules share the same binding motifs: HOH794 binds to the side chain carboxamide NH of Asn 194, and HOH822 binds to the backbone NH of Phe 231 as well as to the side chain amino functionality of Lys 119... HOH890 and its counterpart from PDB 1XUD do not show hydrogen bonding to the MMP‐13 target protein (Figure 5)... Compound represents a novel chemical scaffold with nanomolar inhibitory activity against MMP‐13, which was designed as a chemical scaffold that binds to the biological target by direct hydrogen bonds, as well as through a network of water‐mediated interactions (Figure 8)... In conclusion, we have demonstrated how to use co‐crystal structures of therapeutically relevant proteins very efficiently for the design of inhibitors by targeting multiple water‐mediated interactions with the target protein... By following this rational design concept of targeting multiple structural water molecules as binding partners for small organic molecules, we could enhance the binding affinity of our rationally designed phthalimide scaffold by a factor of 20... This led to a potent and selective nanomolar MMP‐13 inhibitor without any screening activities by a highly decreased number of synthesized compounds compared with classical medicinal chemistry or screening approaches and emphasizes the importance of structural water molecules for the design and discovery of novel small‐molecule inhibitors... We are currently expanding this structural design concept of targeting structural water molecules to other target proteins to show the broad applicability of this approach in the efficient design of novel molecules with tailored biological activity... Details of the synthetic protocols and characterization data for novel compounds can be found in the Supporting Information along with details of the biological methods used to evaluate these compounds.

Show MeSH