Luddite: An Information-Theoretic Library Design Tool

We present an algorithm for the design of either combinatorial or discrete informative libraries. This approach is based on information theoretic techniques used extensively in coding theory. We have extended the information theoretic formalism to include an arbitrary number of property distribution constraints, such as Lipinski "drug-like" distributions. The method is demonstrated by comparing and contrasting a variety of different libraries selected from a single combinatorial source pool of compounds.

[1]  Leach,et al.  The in silico world of virtual libraries. , 2000, Drug discovery today.

[2]  Dimitris K. Agrafiotis.  On the Use of Information Theory for Assessing Molecular Diversity , 1997, J. Chem. Inf. Comput. Sci..

[3]  I. Muegge,et al.  Simple selection criteria for drug-like chemical matter. , 2001, Journal of medicinal chemistry.

[4]  Roger E. Critchlow,et al.  Beyond mere diversity: tailoring combinatorial libraries for drug discovery. , 1999, Journal of combinatorial chemistry.

[5]  Jürgen Bajorath,et al.  Distinguishing between Natural Products and Synthetic Molecules by Descriptor Shannon Entropy Analysis and Binary QSAR Calculations , 2000, J. Chem. Inf. Comput. Sci..

[6]  Dora Schnur,et al.  Design and Diversity Analysis of Large Combinatorial Libraries Using Cell-Based Methods , 1999, J. Chem. Inf. Comput. Sci..

[7]  Robert D. Brown,et al.  Combinatorial library design for diversity, cost efficiency, and drug-like character. , 2000, Journal of molecular graphics & modelling.

[8]  E J Martin,et al.  Oriented substituent pharmacophore PRopErtY space (OSPPREYS): a substituent-based calculation that describes combinatorial library products better than the corresponding product-based calculation. , 2000, Journal of molecular graphics & modelling.

[9]  Jennifer L. Miller,et al.  Combinatorial Library Design: Maximizing Model-Fitting Compounds within Matrix Synthesis Constraints , 2000, J. Chem. Inf. Comput. Sci..

[10]  C. Hansch,et al.  p-σ-π Analysis. A Method for the Correlation of Biological Activity and Chemical Structure , 1964 .

[11]  Thomas M. Cover,et al.  Elements of Information Theory , 2005 .

[12]  P. Beroza,et al.  A rapid computational method for lead evolution: description and application to alpha(1)-adrenergic antagonists. , 2000, Journal of medicinal chemistry.

[13]  Dimitris K. Agrafiotis,et al.  A Constant Time Algorithm for Estimating the Diversity of Large Chemical Libraries , 2001, J. Chem. Inf. Comput. Sci..

[14]  J M Blaney,et al.  Computational approaches for combinatorial library design and molecular diversity analysis. , 1997, Current opinion in chemical biology.

[15]  J W Godden,et al.  Shannon entropy--a novel concept in molecular descriptor and diversity analysis. , 2000, Journal of molecular graphics & modelling.

[16]  Thomas M. Cover,et al.  Introduction and Preview , 2001 .

[17]  Jürgen Bajorath,et al.  Variability of Molecular Descriptors in Compound Databases Revealed by Shannon Entropy Calculations , 2000, J. Chem. Inf. Comput. Sci..

[18]  David C. Spellmeyer,et al.  Chapter 28. Recent Developments in Molecular Diversity: Computational Approaches to Combinatorial Chemistry , 1999 .

[19]  Pickett,et al.  Computational methods for the prediction of 'drug-likeness' , 2000, Drug discovery today.

[20]  Robert L. Patten.  Combinatorics: Topics, Techniques, Algorithms , 1995 .

[21]  Dimitris K. Agrafiotis,et al.  Ultrafast Algorithm for Designing Focused Combinational Arrays , 2000, J. Chem. Inf. Comput. Sci..

[22]  Y. Martin,et al.  Designing combinatorial library mixtures using a genetic algorithm. , 1997, Journal of medicinal chemistry.

[23]  K. M. Smith,et al.  Novel software tools for chemical diversity , 1998 .

[24]  Christian Lemmen,et al.  Coupling structure-based design with combinatorial chemistry: application of active site derived pharmacophores with informative library design. , 2002, Journal of molecular graphics & modelling.

[25]  J. Mason,et al.  The design of combinatorial libraries using properties and 3D pharmacophore fingerprints. , 2001, Drug discovery today.

[26]  Chris L. Waller,et al.  Rational Combinatorial Library Design. 3. Simulated Annealing Guided Evaluation (SAGE) of Molecular Diversity: A Novel Computational Tool for Universal Library Design and Database Mining , 1999, J. Chem. Inf. Comput. Sci..

[27]  H Matter,et al.  Computational approaches towards the rational design of drug-like compound libraries. , 2001, Combinatorial chemistry & high throughput screening.

[28]  D C Spellmeyer,et al.  Measuring diversity: experimental design of combinatorial libraries for drug discovery. , 1995, Journal of medicinal chemistry.

[29]  P Willett,et al.  Chemoinformatics - similarity and diversity in chemical libraries. , 2000, Current opinion in biotechnology.

[30]  Steven L. Teig.  Informative Libraries are More Useful than Diverse Ones , 1998 .

[31]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[32]  Sally Rose.  Statistical design and application to combinatorial chemistry. , 2002, Drug discovery today.

[33]  J. Topliss,et al.  Utilization of operational schemes for analog synthesis in drug design. , 1972, Journal of medicinal chemistry.

[34]  J. Blake,et al.  Chemoinformatics - predicting the physicochemical properties of 'drug-like' molecules. , 2000, Current opinion in biotechnology.