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Prediction of specificity-determining residues for small-molecule kinase inhibitors.

Caffrey DR, Lunney EA, Moshinsky DJ - BMC Bioinformatics (2008)

Bottom Line: S-Filter correctly predicts specificity determinants that were described by independent groups.S-Filter also predicts a number of novel specificity determinants that can often be justified by further structural comparison.The method identifies potential specificity determinants that are not readily apparent, and provokes further investigation at the structural level.

View Article: PubMed Central - HTML - PubMed

Affiliation: Pfizer Research Technology Center, 620 Memorial Drive, Cambridge, MA 02139, USA. daniel.caffrey@gmail.com

ABSTRACT

Background: Designing small-molecule kinase inhibitors with desirable selectivity profiles is a major challenge in drug discovery. A high-throughput screen for inhibitors of a given kinase will typically yield many compounds that inhibit more than one kinase. A series of chemical modifications are usually required before a compound exhibits an acceptable selectivity profile. Rationalizing the selectivity profile for a small-molecule inhibitor in terms of the specificity-determining kinase residues for that molecule can be an important step toward the goal of developing selective kinase inhibitors.

Results: Here we describe S-Filter, a method that combines sequence and structural information to predict specificity-determining residues for a small molecule and its kinase selectivity profile. Analysis was performed on seven selective kinase inhibitors where a structural basis for selectivity is known. S-Filter correctly predicts specificity determinants that were described by independent groups. S-Filter also predicts a number of novel specificity determinants that can often be justified by further structural comparison.

Conclusion: S-Filter is a valuable tool for analyzing kinase selectivity profiles. The method identifies potential specificity determinants that are not readily apparent, and provokes further investigation at the structural level.

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Structural basis for Roscovitine selectivity. The 3D structure of p38 (PDB 2GTM, wire rendering with grey carbons) was superposed onto the structure of CDK2 (hidden) in complex with Roscovitine (PDB 2A4L, ball and stick rendering with green carbons). Roscovitine appears to clash (orange lines) with Leu 167 (ball and stick rendering with grey carbons) of p38. Importantly, Leu 167 is buried deep in the pocket where there is little room to maneuver. In contrast, Ala 144 (stick rendering with green carbons) of CDK2 accommodates the compound. Based on this putative steric clash, we propose that S-Filter correctly predicted Ala 144 as specificity determinant for Roscovitine.
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Figure 6: Structural basis for Roscovitine selectivity. The 3D structure of p38 (PDB 2GTM, wire rendering with grey carbons) was superposed onto the structure of CDK2 (hidden) in complex with Roscovitine (PDB 2A4L, ball and stick rendering with green carbons). Roscovitine appears to clash (orange lines) with Leu 167 (ball and stick rendering with grey carbons) of p38. Importantly, Leu 167 is buried deep in the pocket where there is little room to maneuver. In contrast, Ala 144 (stick rendering with green carbons) of CDK2 accommodates the compound. Based on this putative steric clash, we propose that S-Filter correctly predicted Ala 144 as specificity determinant for Roscovitine.

Mentions: To the best of our knowledge, this is the first time that Ala 144 has been proposed as a selectivity-determining residue. When p38 is superposed onto CDK2, Roscovitine appears to clash with Leu 167 of p38 (Figure 6). This putative steric clash suggests that a bulkier residue in place of Ala 144 will not accommodate Roscovitine. Based on this putative steric clash, we propose that S-Filter correctly predicted Ala 144 and we self-designate the prediction as a true positive in Table 1. The remaining predictions are regarded as false positives. In summary, the above observations suggest that one of the three predictions are correct.


Prediction of specificity-determining residues for small-molecule kinase inhibitors.

Caffrey DR, Lunney EA, Moshinsky DJ - BMC Bioinformatics (2008)

Structural basis for Roscovitine selectivity. The 3D structure of p38 (PDB 2GTM, wire rendering with grey carbons) was superposed onto the structure of CDK2 (hidden) in complex with Roscovitine (PDB 2A4L, ball and stick rendering with green carbons). Roscovitine appears to clash (orange lines) with Leu 167 (ball and stick rendering with grey carbons) of p38. Importantly, Leu 167 is buried deep in the pocket where there is little room to maneuver. In contrast, Ala 144 (stick rendering with green carbons) of CDK2 accommodates the compound. Based on this putative steric clash, we propose that S-Filter correctly predicted Ala 144 as specificity determinant for Roscovitine.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2655090&req=5

Figure 6: Structural basis for Roscovitine selectivity. The 3D structure of p38 (PDB 2GTM, wire rendering with grey carbons) was superposed onto the structure of CDK2 (hidden) in complex with Roscovitine (PDB 2A4L, ball and stick rendering with green carbons). Roscovitine appears to clash (orange lines) with Leu 167 (ball and stick rendering with grey carbons) of p38. Importantly, Leu 167 is buried deep in the pocket where there is little room to maneuver. In contrast, Ala 144 (stick rendering with green carbons) of CDK2 accommodates the compound. Based on this putative steric clash, we propose that S-Filter correctly predicted Ala 144 as specificity determinant for Roscovitine.
Mentions: To the best of our knowledge, this is the first time that Ala 144 has been proposed as a selectivity-determining residue. When p38 is superposed onto CDK2, Roscovitine appears to clash with Leu 167 of p38 (Figure 6). This putative steric clash suggests that a bulkier residue in place of Ala 144 will not accommodate Roscovitine. Based on this putative steric clash, we propose that S-Filter correctly predicted Ala 144 and we self-designate the prediction as a true positive in Table 1. The remaining predictions are regarded as false positives. In summary, the above observations suggest that one of the three predictions are correct.

Bottom Line: S-Filter correctly predicts specificity determinants that were described by independent groups.S-Filter also predicts a number of novel specificity determinants that can often be justified by further structural comparison.The method identifies potential specificity determinants that are not readily apparent, and provokes further investigation at the structural level.

View Article: PubMed Central - HTML - PubMed

Affiliation: Pfizer Research Technology Center, 620 Memorial Drive, Cambridge, MA 02139, USA. daniel.caffrey@gmail.com

ABSTRACT

Background: Designing small-molecule kinase inhibitors with desirable selectivity profiles is a major challenge in drug discovery. A high-throughput screen for inhibitors of a given kinase will typically yield many compounds that inhibit more than one kinase. A series of chemical modifications are usually required before a compound exhibits an acceptable selectivity profile. Rationalizing the selectivity profile for a small-molecule inhibitor in terms of the specificity-determining kinase residues for that molecule can be an important step toward the goal of developing selective kinase inhibitors.

Results: Here we describe S-Filter, a method that combines sequence and structural information to predict specificity-determining residues for a small molecule and its kinase selectivity profile. Analysis was performed on seven selective kinase inhibitors where a structural basis for selectivity is known. S-Filter correctly predicts specificity determinants that were described by independent groups. S-Filter also predicts a number of novel specificity determinants that can often be justified by further structural comparison.

Conclusion: S-Filter is a valuable tool for analyzing kinase selectivity profiles. The method identifies potential specificity determinants that are not readily apparent, and provokes further investigation at the structural level.

Show MeSH