Applications of random sampling to virtual screening of combinatorial libraries

Beroza, Paul; Bradley, Erin K.; Eksterowicz, John; Feinstein, Robert; Greene, Jonathan; Grootenhuis, Peter D. J.; Henne, Randal M.; Mount, John; Shirley, William A.; Smellie, Andrew; Stanton, Robert V.; Spellmeyer, David C.

doi:10.1016/s1093-3263(00)80090-x

Cited by 10 publications

(10 citation statements)

References 32 publications

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“…It is possible to compare these results with the work of Beroza et al and their Lockdown approach. They have optimized a 9 × 461 × 2285 × 1372 Ugi library and needed only 185 000 property evaluations of products.…”

Section: Partitioning Techniquementioning

confidence: 84%

GLARE: A New Approach for Filtering Large Reagent Lists in Combinatorial Library Design Using Product Properties

Truchon

Bayly

2006

J. Chem. Inf. Model.

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We present a novel computer algorithm, called GLARE (Global Library Assessment of REagents), that addresses the issue of optimal reagent selection in combinatorial library design. This program reduces or eliminates the time a medicinal chemist spends examining reagents which a priori cannot be part of a "good" library. Our approach takes the large reagent sets returned by standard chemical database queries and produces often considerably reduced reagent sets that are well-behaved with respect to a specific template. The pruning enforces "goodness" constraints such as the Lipinski rule of five on the product properties such that any reagent selection from the resulting sets produces only "good" products. The algorithm we implemented has three important features: (i) As opposed to genetic algorithms or other stochastic algorithms, GLARE uses a deterministic greedy procedure that smoothly filters out nonviable reagents. (ii) The pruning method can be biased to produce reagent sets with a balanced size, conserving proportionally more reagents in smaller sets. (iii) For very large combinatorial libraries, a partitioning scheme allows libraries as large as 10(12) to be evaluated in 0.25 s on an IBM AMD Opteron processor. This algorithm is validated on a diverse set of 12 libraries. The results that we obtained show an excellent compliance to the product property requirements and very fast timings.

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Section: Partitioning Techniquementioning

confidence: 84%

GLARE: A New Approach for Filtering Large Reagent Lists in Combinatorial Library Design Using Product Properties

Truchon

Bayly

2006

J. Chem. Inf. Model.

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“…Focused libraries are enriched for a desired target and are more amenable to chemical synthesis, purification, analysis, and finally assaying to verify the efficacy of the focusing process [88]. The rational selection of compounds for these libraries leads to efficiency and economy in the screening process as compared to the random nature of HTS.…”

Section: Discussionmentioning

confidence: 99%

Pharmacophore Modeling Methods in Focused Library Selection – Applications in the Context of a New Classification Scheme

Luu¹,

Malcolm²,

Nadassy³

2011

CCHTS

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A pharmacophore is a model which represents the key physico-chemical interactions that mediate biological activity. There is a long history of using pharmacophore modeling methods to select subsets of compounds, focused towards a specific target of interest. This paper will review existing computational methods for deriving and comparing pharmacophore models. We outline a new classification of pharmacophore methods based on the abstraction of the underlying chemical interactions which embody a pharmacophore, and the methods available to quantitatively compare them. Within the context of this classification, example studies, using specific pharmacophore modeling methods for focused library selection, will be discussed.

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“…The hypotheses were then ranked based on their ability to discriminate between actives and inactives across the entire data set. The ranking criterion used was 'information content', [12] a function of both the active and inactive compounds. The top 100 pharmacophores were used to analyze virtual chemical libraries and to select compounds for the next round of synthesis and screening.…”

Section: Discussionmentioning

confidence: 99%

Lead-Discovery of bis-Aromatic Alkynes: A Novel Class of Herbicides

Glock¹,

Allen²,

Niderman³

et al. 2008

Chimia

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The search for new active molecules with novel modes of action and desirable physical properties is an ongoing endeavour. This publication describes the follow-up chemistry of a biological hit discovered in the screening system of Novartis Crop Protection, the legacy agrochemical parent of Syngenta Crop Protection. This chemistry was optimized through classical synthetic methods and automated parallel synthesis with coverage of important physical properties such as lipophilicity or Clog P and solubility. Preliminary biological activity from the greenhouse and field data with symptomology is presented.

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Applications of random sampling to virtual screening of combinatorial libraries

Cited by 10 publications

References 32 publications

GLARE: A New Approach for Filtering Large Reagent Lists in Combinatorial Library Design Using Product Properties

GLARE: A New Approach for Filtering Large Reagent Lists in Combinatorial Library Design Using Product Properties

Pharmacophore Modeling Methods in Focused Library Selection – Applications in the Context of a New Classification Scheme

Lead-Discovery of bis-Aromatic Alkynes: A Novel Class of Herbicides

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