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Exploring fragment spaces under multiple physicochemical constraints

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Abstract

We present a new algorithm for the enumeration of chemical fragment spaces under constraints. Fragment spaces consist of a set of molecular fragments and a set of rules that specifies how fragments can be combined. Although fragment spaces typically cover an infinite number of molecules, they can be enumerated in case that a physicochemical profile of the requested compounds is given. By using min–max ranges for a number of corresponding properties, our algorithm is able to enumerate all molecules which obey these properties. To speed up the calculation, the given ranges are used directly during the build-up process to guide the selection of fragments. Furthermore, a topology based fragment filter is used to skip most of the redundant fragment combinations. We applied the algorithm to 40 different target classes. For each of these, we generated tailored fragment spaces from sets of known inhibitors and additionally derived ranges for several physicochemical properties. We characterized the target-specific fragment spaces and were able to enumerate the complete chemical subspaces for most of the targets.

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Abbreviations

ACE:

Angiotensin-converting enzyme

AChE:

Acetylcholinesterase

ADA:

Adenosine deaminase

ALR2:

Aldose reductase

AmpC:

AmpC β-lactamase

AR:

Androgen receptor

CDK2:

Cyclin-dependent kinase 2

COMT:

Catechol O-methyltransferase

COX-1:

Cyclooxygenase-1

COX-2:

Cyclooxygenase-2

DHFR:

Dihydrofolate reductase

EGFr:

Epidermal growth factor receptor

ER:

Estrogen receptor

FGFr1:

Fibroblast growth factor receptor kinase

FXa:

Factor Xa

GART:

Glycinamide ribonucleotide transformylase

GPB:

Glycogen phosphorylase β

GR:

Glucocorticoid receptor

HIVPR:

HIV protease

HIVRT:

HIV reverse transcriptase

HMGR:

Hydroxymethylglutaryl-CoA reductase

HSP90:

Human heat shock protein 90

InhA:

Enoyl ACP reductase

MR:

Mineralocorticoid receptor

NA:

Neuraminidase

P38 MAP:

P38 mitogen activated protein

PARP:

Poly(ADP-ribose) polymerase

PDE5:

Phosphodiesterase 5

PDGFrb:

Platelet derived growth factor receptor kinase

PNP:

Purine nucleoside phosphorylase

PPARg:

Peroxisome proliferator activated receptor γ

PR:

Progesterone receptor

RXRa:

Retinoic X receptor α

SAHH:

S-adenosyl-homocysteine hydrolase

SRC:

Tyrosine kinase SRC

TK:

Thymidine kinase

VEGFr2:

Vascular endothelial growth factor receptor

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Acknowledgments

The authors thank Andrea Zaliani (Lilly Research Laboratories, Hamburg, Germany) for careful reading of the manuscript and Tora Pommerencke, Christoph Müller and Florian Krull, who developed some useful ideas how to improve the performance of the enumeration during their time as project students. Additionally, we thank Patrick Maaß for help in generating the fragments out of the inhibitors sets. We further thank all partners in the NovoBench project for fruitful feedback and the german federal ministry of education and research for funding (grant 313324A).

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Authors and Affiliations

  1. Center for Bioinformatics, Bundesstrasse 43, 20146, Hamburg, Germany

    Juri Pärn, Jörg Degen & Matthias Rarey

Authors
  1. Juri Pärn
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  2. Jörg Degen
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  3. Matthias Rarey
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Correspondence to Matthias Rarey.

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Pärn, J., Degen, J. & Rarey, M. Exploring fragment spaces under multiple physicochemical constraints. J Comput Aided Mol Des 21, 327–340 (2007). https://doi.org/10.1007/s10822-007-9121-3

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  • DOI: https://doi.org/10.1007/s10822-007-9121-3

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