SPROUT: Recent developments in the de novo design of molecules

Gillet, Valerie J.; Newell, William R.; Mata, Paulina; Myatt, Glenn J.; Sike, Sandor; Zsoldos, Zsolt; Johnson, A. Peter

doi:10.1021/ci00017a027

Cited by 169 publications

(107 citation statements)

References 5 publications

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“…Ligand docking Prediction of bound Manuel docking, ligand conformation DOCK, [6] Flex-X [7] GOLD [8] Receptor interaction Ligand optimization GRID, [9] MCSS, [10] mapping RELIBASE, [11] SUPERSTAR [12] Scoring Affinity prediction GLIDE, GOLD, LUDI, [13] DOCKSCORE, [14] SmoG2001 [15] 3D QSAR Affinity prediction CATALYST, [16] COMFA, [17] GOLPE [18] De novo design Automated ligand LEAPFROG, [19] LUDI design CombiSMoG, [20] SPROUT [21] Pharmacophore Potential lead retrieval CATALYST, UNITY [22] searching from real or virtual databases…”

Section: Technologymentioning

confidence: 99%

Application and Limitations of X‐ray Crystallographic Data in Structure‐Based Ligand and Drug Design

2003

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Structure-based design usually focuses upon the optimization of ligand affinity. However, successful drug design also requires the optimization of many other properties. The primary source of structural information for protein-ligand complexes is X-ray crystallography. The uncertainties introduced during the derivation of an atomic model from the experimentally observed electron density data are not always appreciated. Uncertainties in the atomic model can have significant consequences when this model is subsequently used as the basis of manual design, docking, scoring, and virtual screening efforts. Docking and scoring algorithms are currently imperfect. A good correlation between observed and calculated binding affinities is usually only observed only when very large ranges of affinity are considered. Errors in the correlation often exceed the range of affinities commonly encountered during lead optimization. Some structure-based design approaches now involve screening libraries by using technologies based on NMR spectroscopy and X-ray crystallography to discover small polar templates, which are used for further optimization. Such compounds are defined as leadlike and are also sought by more traditional high-throughput screening technologies. Structure-based design and HTS technologies show important complementarity and a degree of convergence.

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Section: Technologymentioning

confidence: 99%

Application and Limitations of X‐ray Crystallographic Data in Structure‐Based Ligand and Drug Design

2003

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“…Programs adopting this approach differ in the way they combine templates and the type of method they use for the treatment of conformational flexibility. Two programs that work in a stepwise manner are, for example, SPROUT, [14][15][16] which is based on graph-searching algorithms, and Skelgen, [17,18] which uses a Monte Carlo-type method. Other approaches fit molecular fragments, functional groups, or atoms onto previously determined interaction sites within the protein cavity.…”

Section: Introductionmentioning

confidence: 99%

FlexNovo: Structure‐Based Searching in Large Fragment Spaces

Degen

Rarey

2006

ChemMedChem

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We present a new molecular design program, FlexNovo, for structure-based searching within large fragment spaces following a sequential growth strategy. The fragment spaces consist of several thousands of chemical fragments and a corresponding set of rules that specify how the fragments can be connected. FlexNovo is based on the FlexX molecular docking software and makes use of its incremental construction algorithm and the underlying chemical models. Interaction energies are calculated by using standard scoring functions. Several placement geometry, physicochemical property (drug-likeness), and diversity filter criteria are directly integrated into the "build-up" process. FlexNovo has been used to design potential inhibitors for four targets of pharmaceutical interest (dihydrofolate reductase, cyclin-dependant kinase 2, cyclooxygenase-2, and the estrogen receptor). We have carried out calculations using different diversity parameters for each of these targets and generated solution sets containing up to 50 molecules. The compounds obtained show that FlexNovo is able to generate a diverse set of reasonable molecules with drug-like properties. The results, including an automated similarity analysis with the Feature Tree program, indicate that FlexNovo often reproduces structural motifs as well as the corresponding binding modes seen in known active structures.

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“…[19][20][21] Here, we present the studies of a new BACE1 inhibitor scaffold designed using the de novo molecular design program SPROUT. 22,23 A library of structural analogs of the initial designed skeleton was synthesized and tested against recombinant BACE1. SAR analysis and ligand optimization of this library of compounds were achieved using hit optimization software SPROUT-HitOpt.…”

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confidence: 99%

Discovery of Biphenylacetamide-Derived Inhibitors of BACE1 Using de Novo Structure-Based Molecular Design

et al. 2013

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Beta-secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-beta peptides, is an attractive target for the treatment of Alzheimer's disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of non-peptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC 50 of 323 M to 27 M following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity.This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors.3

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SPROUT: Recent developments in the de novo design of molecules

Cited by 169 publications

References 5 publications

Application and Limitations of X‐ray Crystallographic Data in Structure‐Based Ligand and Drug Design

Application and Limitations of X‐ray Crystallographic Data in Structure‐Based Ligand and Drug Design

FlexNovo: Structure‐Based Searching in Large Fragment Spaces

Discovery of Biphenylacetamide-Derived Inhibitors of BACE1 Using de Novo Structure-Based Molecular Design

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