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Increasing chemical space coverage by combining empirical and computational fragment screens.

Barelier S, Eidam O, Fish I, Hollander J, Figaroa F, Nachane R, Irwin JJ, Shoichet BK, Siegal G - ACS Chem. Biol. (2014)

Bottom Line: Crystal structures of nine of the fragments in complex with AmpC β-lactamase revealed new binding sites and explained the relatively high affinity of the docking-derived fragments.The existence of chemotype holes is likely a general feature of fragment libraries, as calculation suggests that to represent the fragment substructures of even known biogenic molecules would demand a library of minimally over 32,000 fragments.Combining computational and empirical fragment screens enables the discovery of unexpected chemotypes, here by the NMR screen, while capturing chemotypes missing from the empirical library and tailored to the target, with little extra cost in resources.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco , 1700 4th St., Byers Hall, San Francisco, California 94158, United States.

ABSTRACT
Most libraries for fragment-based drug discovery are restricted to 1,000-10,000 compounds, but over 500,000 fragments are commercially available and potentially accessible by virtual screening. Whether this larger set would increase chemotype coverage, and whether a computational screen can pragmatically prioritize them, is debated. To investigate this question, a 1281-fragment library was screened by nuclear magnetic resonance (NMR) against AmpC β-lactamase, and hits were confirmed by surface plasmon resonance (SPR). Nine hits with novel chemotypes were confirmed biochemically with KI values from 0.2 to low mM. We also computationally docked 290,000 purchasable fragments with chemotypes unrepresented in the empirical library, finding 10 that had KI values from 0.03 to low mM. Though less novel than those discovered by NMR, the docking-derived fragments filled chemotype holes from the empirical library. Crystal structures of nine of the fragments in complex with AmpC β-lactamase revealed new binding sites and explained the relatively high affinity of the docking-derived fragments. The existence of chemotype holes is likely a general feature of fragment libraries, as calculation suggests that to represent the fragment substructures of even known biogenic molecules would demand a library of minimally over 32,000 fragments. Combining computational and empirical fragment screens enables the discovery of unexpected chemotypes, here by the NMR screen, while capturing chemotypes missing from the empirical library and tailored to the target, with little extra cost in resources.

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Related in: MedlinePlus

Fragments tilingsubstructures of biogenic molecules. (a) Threerepresentative ZINC fragments that are substructures of Imatinib.(b) Three representative ZINC fragments that are substructures ofDB07833 (p38 MAP Kinase inhibitor). Fragment 19257754 in Imatinibis similar to fragment 3518745 in DB07833 in chemical path fingerprints(CP Tc = 0.725; ECFP_4 Tc = 0.402), and only one of them was keptin the maximally diverse fragment set (see column 4 in Table 2).
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fig4: Fragments tilingsubstructures of biogenic molecules. (a) Threerepresentative ZINC fragments that are substructures of Imatinib.(b) Three representative ZINC fragments that are substructures ofDB07833 (p38 MAP Kinase inhibitor). Fragment 19257754 in Imatinibis similar to fragment 3518745 in DB07833 in chemical path fingerprints(CP Tc = 0.725; ECFP_4 Tc = 0.402), and only one of them was keptin the maximally diverse fragment set (see column 4 in Table 2).

Mentions: A totalof 458,329 ZINC fragments were compared to these three sets of bioactivemolecules;35 fragments were accepted assubstructures if they matched a full substructure of any molecule,with a small tolerance of variability. To tile the bioactive moleculeswith fragments, allowing for some tolerance, we insisted on Tverskysimilarity of ≥ 0.6; this metric is widely used to comparefragments to larger molecules36 (Figure 4 and Supplementary Table 6). Having found all purchasable fragments that match substructuresamong drugs, metabolites, and natural products (Table 2, column 3), we applied the dissimilarity criterion to arriveat a diverse set (Figure 4 and Table 2, column 4). Over 6,000 fragments are substructuresof the FDA-approved drugs only. To tile all drugs, metabolites andnatural products, 32,323 fragments are needed. Full-coverage fragmentlibraries have thus been created and made available here (http://zinc.docking.org/full_space_fragments/ and as Supporting Information).


Increasing chemical space coverage by combining empirical and computational fragment screens.

Barelier S, Eidam O, Fish I, Hollander J, Figaroa F, Nachane R, Irwin JJ, Shoichet BK, Siegal G - ACS Chem. Biol. (2014)

Fragments tilingsubstructures of biogenic molecules. (a) Threerepresentative ZINC fragments that are substructures of Imatinib.(b) Three representative ZINC fragments that are substructures ofDB07833 (p38 MAP Kinase inhibitor). Fragment 19257754 in Imatinibis similar to fragment 3518745 in DB07833 in chemical path fingerprints(CP Tc = 0.725; ECFP_4 Tc = 0.402), and only one of them was keptin the maximally diverse fragment set (see column 4 in Table 2).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215856&req=5

fig4: Fragments tilingsubstructures of biogenic molecules. (a) Threerepresentative ZINC fragments that are substructures of Imatinib.(b) Three representative ZINC fragments that are substructures ofDB07833 (p38 MAP Kinase inhibitor). Fragment 19257754 in Imatinibis similar to fragment 3518745 in DB07833 in chemical path fingerprints(CP Tc = 0.725; ECFP_4 Tc = 0.402), and only one of them was keptin the maximally diverse fragment set (see column 4 in Table 2).
Mentions: A totalof 458,329 ZINC fragments were compared to these three sets of bioactivemolecules;35 fragments were accepted assubstructures if they matched a full substructure of any molecule,with a small tolerance of variability. To tile the bioactive moleculeswith fragments, allowing for some tolerance, we insisted on Tverskysimilarity of ≥ 0.6; this metric is widely used to comparefragments to larger molecules36 (Figure 4 and Supplementary Table 6). Having found all purchasable fragments that match substructuresamong drugs, metabolites, and natural products (Table 2, column 3), we applied the dissimilarity criterion to arriveat a diverse set (Figure 4 and Table 2, column 4). Over 6,000 fragments are substructuresof the FDA-approved drugs only. To tile all drugs, metabolites andnatural products, 32,323 fragments are needed. Full-coverage fragmentlibraries have thus been created and made available here (http://zinc.docking.org/full_space_fragments/ and as Supporting Information).

Bottom Line: Crystal structures of nine of the fragments in complex with AmpC β-lactamase revealed new binding sites and explained the relatively high affinity of the docking-derived fragments.The existence of chemotype holes is likely a general feature of fragment libraries, as calculation suggests that to represent the fragment substructures of even known biogenic molecules would demand a library of minimally over 32,000 fragments.Combining computational and empirical fragment screens enables the discovery of unexpected chemotypes, here by the NMR screen, while capturing chemotypes missing from the empirical library and tailored to the target, with little extra cost in resources.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco , 1700 4th St., Byers Hall, San Francisco, California 94158, United States.

ABSTRACT
Most libraries for fragment-based drug discovery are restricted to 1,000-10,000 compounds, but over 500,000 fragments are commercially available and potentially accessible by virtual screening. Whether this larger set would increase chemotype coverage, and whether a computational screen can pragmatically prioritize them, is debated. To investigate this question, a 1281-fragment library was screened by nuclear magnetic resonance (NMR) against AmpC β-lactamase, and hits were confirmed by surface plasmon resonance (SPR). Nine hits with novel chemotypes were confirmed biochemically with KI values from 0.2 to low mM. We also computationally docked 290,000 purchasable fragments with chemotypes unrepresented in the empirical library, finding 10 that had KI values from 0.03 to low mM. Though less novel than those discovered by NMR, the docking-derived fragments filled chemotype holes from the empirical library. Crystal structures of nine of the fragments in complex with AmpC β-lactamase revealed new binding sites and explained the relatively high affinity of the docking-derived fragments. The existence of chemotype holes is likely a general feature of fragment libraries, as calculation suggests that to represent the fragment substructures of even known biogenic molecules would demand a library of minimally over 32,000 fragments. Combining computational and empirical fragment screens enables the discovery of unexpected chemotypes, here by the NMR screen, while capturing chemotypes missing from the empirical library and tailored to the target, with little extra cost in resources.

Show MeSH
Related in: MedlinePlus