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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 SB-203580 selectivity. The 3D structure of Abl (PDB 1M52, wire rendering with grey carbons) was superposed onto the structure of p38 (hidden) in complex with SB-203580 (PDB 1A9U, ball and stick rendering with green carbons). Like p38, Abl has a Thr at the gatekeeper position and suggests that there are other selectivity determinants that prevent SB-203580 from inhibiting Abl. The fluorophenyl of SB-203580 appears to clash (orange lines) with Ile 313 (ball and stick rendering with grey carbons) of Abl. In contrast, Leu 104 (stick rendering with green carbons) of p38 accommodates the compound. Importantly, the isoleucine is deep in the pocket where other isoleucine rotamers are likely to clash with other residues in Abl. Based on this putative steric clash, we propose that S-Filter correctly predicted Leu 104 as specificity determinant for Roscovitine.
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Figure 4: Structural basis for SB-203580 selectivity. The 3D structure of Abl (PDB 1M52, wire rendering with grey carbons) was superposed onto the structure of p38 (hidden) in complex with SB-203580 (PDB 1A9U, ball and stick rendering with green carbons). Like p38, Abl has a Thr at the gatekeeper position and suggests that there are other selectivity determinants that prevent SB-203580 from inhibiting Abl. The fluorophenyl of SB-203580 appears to clash (orange lines) with Ile 313 (ball and stick rendering with grey carbons) of Abl. In contrast, Leu 104 (stick rendering with green carbons) of p38 accommodates the compound. Importantly, the isoleucine is deep in the pocket where other isoleucine rotamers are likely to clash with other residues in Abl. Based on this putative steric clash, we propose that S-Filter correctly predicted Leu 104 as specificity determinant for Roscovitine.

Mentions: However, three of the kinases that have a threonine at the gatekeeper position are not inhibited by SB-203580, indicating that there are additional specificity determinants. To the best of our knowledge, this is the first time that Leu 104 has been proposed as a selectivity-determining residue. Following this prediction, we explored the consequences of SRC, LCK, and ABL having an isoleucine in place of Leu 104. When ABL is superposed onto the structure of p38-SB-203580, the isoleucine of ABL appears to clash with the fluorophenyl of SB-203580 (Figure 4). In contrast, Leu 104 of p38 is free to rotate its side chain and accommodate the fluorophenyl. Based on this putative steric clash, we propose that S-Filter correctly predicted Leu 104 and we self-designate the prediction as a true positive in Table 1. This prediction demonstrates S-Filter's ability to flag selectivity determinants that have been overlooked by previous efforts. In this case, key information was derived from the multiple sequence alignment. In summary, the above observations suggest that the two 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 SB-203580 selectivity. The 3D structure of Abl (PDB 1M52, wire rendering with grey carbons) was superposed onto the structure of p38 (hidden) in complex with SB-203580 (PDB 1A9U, ball and stick rendering with green carbons). Like p38, Abl has a Thr at the gatekeeper position and suggests that there are other selectivity determinants that prevent SB-203580 from inhibiting Abl. The fluorophenyl of SB-203580 appears to clash (orange lines) with Ile 313 (ball and stick rendering with grey carbons) of Abl. In contrast, Leu 104 (stick rendering with green carbons) of p38 accommodates the compound. Importantly, the isoleucine is deep in the pocket where other isoleucine rotamers are likely to clash with other residues in Abl. Based on this putative steric clash, we propose that S-Filter correctly predicted Leu 104 as specificity determinant for Roscovitine.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Structural basis for SB-203580 selectivity. The 3D structure of Abl (PDB 1M52, wire rendering with grey carbons) was superposed onto the structure of p38 (hidden) in complex with SB-203580 (PDB 1A9U, ball and stick rendering with green carbons). Like p38, Abl has a Thr at the gatekeeper position and suggests that there are other selectivity determinants that prevent SB-203580 from inhibiting Abl. The fluorophenyl of SB-203580 appears to clash (orange lines) with Ile 313 (ball and stick rendering with grey carbons) of Abl. In contrast, Leu 104 (stick rendering with green carbons) of p38 accommodates the compound. Importantly, the isoleucine is deep in the pocket where other isoleucine rotamers are likely to clash with other residues in Abl. Based on this putative steric clash, we propose that S-Filter correctly predicted Leu 104 as specificity determinant for Roscovitine.
Mentions: However, three of the kinases that have a threonine at the gatekeeper position are not inhibited by SB-203580, indicating that there are additional specificity determinants. To the best of our knowledge, this is the first time that Leu 104 has been proposed as a selectivity-determining residue. Following this prediction, we explored the consequences of SRC, LCK, and ABL having an isoleucine in place of Leu 104. When ABL is superposed onto the structure of p38-SB-203580, the isoleucine of ABL appears to clash with the fluorophenyl of SB-203580 (Figure 4). In contrast, Leu 104 of p38 is free to rotate its side chain and accommodate the fluorophenyl. Based on this putative steric clash, we propose that S-Filter correctly predicted Leu 104 and we self-designate the prediction as a true positive in Table 1. This prediction demonstrates S-Filter's ability to flag selectivity determinants that have been overlooked by previous efforts. In this case, key information was derived from the multiple sequence alignment. In summary, the above observations suggest that the two 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