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Evaluating the predictivity of virtual screening for ABL kinase inhibitors to hinder drug resistance.

Gani OA, Narayanan D, Engh RA - Chem Biol Drug Des (2013)

Bottom Line: However, any practical ligand set (of active or inactive compounds) chosen for deriving new virtual screening approaches cannot fully represent all relevant chemical space for potential new compounds.We show how various scoring functions and choice of inactive ligand sets influence overall and early enrichment of the libraries.We believe that this study can be extended to other therapeutically important kinases in prospective virtual screening studies.

View Article: PubMed Central - PubMed

Affiliation: The Norwegian Structural Biology Center, Department of Chemistry, University of Tromsø, 9037, Tromsø, Norway.

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Chemical spaces occupied by active inhibitor and decoys. About 40 molecular properties were summarized to eight principal components (PCs), and three major PCs were mapped in three-axes of Cartesian coordinates. (A) Color coded as blue is for randomly selected potent kinase inhibitors, green is for Directory of Useful Decoys (DUD) decoys, and red is for highly potent dual activity ABL1 inhibitors. (B) Blue is for ABL1-wt and red for ABL1-T315I. PC1, which is predominantly size, shape, and polarizability, distinguishes DUD decoys and inhibitors most.
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fig06: Chemical spaces occupied by active inhibitor and decoys. About 40 molecular properties were summarized to eight principal components (PCs), and three major PCs were mapped in three-axes of Cartesian coordinates. (A) Color coded as blue is for randomly selected potent kinase inhibitors, green is for Directory of Useful Decoys (DUD) decoys, and red is for highly potent dual activity ABL1 inhibitors. (B) Blue is for ABL1-wt and red for ABL1-T315I. PC1, which is predominantly size, shape, and polarizability, distinguishes DUD decoys and inhibitors most.

Mentions: Despite some overlap, active inhibitors and DUD decoys map to distinguishable volumes in chemical space (Figure6A). This itself provides information to filter sets of potential inhibitors to eliminate compounds that match decoys rather than inhibitors. In contrast, plotting ABL1-wt selective inhibitors versus dual active ABL1 inhibitors does not distinguish the sets (Figure6B) in the major PC dimensions.


Evaluating the predictivity of virtual screening for ABL kinase inhibitors to hinder drug resistance.

Gani OA, Narayanan D, Engh RA - Chem Biol Drug Des (2013)

Chemical spaces occupied by active inhibitor and decoys. About 40 molecular properties were summarized to eight principal components (PCs), and three major PCs were mapped in three-axes of Cartesian coordinates. (A) Color coded as blue is for randomly selected potent kinase inhibitors, green is for Directory of Useful Decoys (DUD) decoys, and red is for highly potent dual activity ABL1 inhibitors. (B) Blue is for ABL1-wt and red for ABL1-T315I. PC1, which is predominantly size, shape, and polarizability, distinguishes DUD decoys and inhibitors most.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4265857&req=5

fig06: Chemical spaces occupied by active inhibitor and decoys. About 40 molecular properties were summarized to eight principal components (PCs), and three major PCs were mapped in three-axes of Cartesian coordinates. (A) Color coded as blue is for randomly selected potent kinase inhibitors, green is for Directory of Useful Decoys (DUD) decoys, and red is for highly potent dual activity ABL1 inhibitors. (B) Blue is for ABL1-wt and red for ABL1-T315I. PC1, which is predominantly size, shape, and polarizability, distinguishes DUD decoys and inhibitors most.
Mentions: Despite some overlap, active inhibitors and DUD decoys map to distinguishable volumes in chemical space (Figure6A). This itself provides information to filter sets of potential inhibitors to eliminate compounds that match decoys rather than inhibitors. In contrast, plotting ABL1-wt selective inhibitors versus dual active ABL1 inhibitors does not distinguish the sets (Figure6B) in the major PC dimensions.

Bottom Line: However, any practical ligand set (of active or inactive compounds) chosen for deriving new virtual screening approaches cannot fully represent all relevant chemical space for potential new compounds.We show how various scoring functions and choice of inactive ligand sets influence overall and early enrichment of the libraries.We believe that this study can be extended to other therapeutically important kinases in prospective virtual screening studies.

View Article: PubMed Central - PubMed

Affiliation: The Norwegian Structural Biology Center, Department of Chemistry, University of Tromsø, 9037, Tromsø, Norway.

Show MeSH
Related in: MedlinePlus