Algorithmic strategies in combinatorial chemistry

Combinatorial Chemistry is a powerful new technology in drug design and molecular recognition. It is a wet-laboratory methodology aimed at ``massively parallel'' screening of chemical compounds for the discovery of compounds that have a certain biological activity. The power of the method comes from the interaction between experimental design and computational modeling. Principles of ``rational'' drug design are used in the construction of combinatorial libraries to speed up the discovery of lead compounds with the desired biological activity. This paper presents algorithms, software development and computational complexity analysis for problems arising in the design of combinatorial libraries for drug discovery. The authors provide exact polynomial time algorithms and intractability results for several Inverse Problems-formulated as (chemical) graph reconstruction problems-related to the design of combinatorial libraries. These are the first rigorous algorithmic results in the literature. The authors also present results provided by the combinatorial chemistry software package OCOTILLO for combinatorial peptide design using real data libraries. The package provides exact solutions for general inverse problems based on shortest-path topological indices. The results are superior both in accuracy and computing time to the best software reports published in the literature. For 5-peptoid design, the computation is rigorously reduced to an exhaustive search of about 2% of the search space; the exact solutions are found in a few minutes.

[1]  H. Wiener.  Structural determination of paraffin boiling points. , 1947, Journal of the American Chemical Society.

[2]  R. Venkataraghavan,et al.  Atom pairs as molecular features in structure-activity studies: definition and applications , 1985, J. Chem. Inf. Comput. Sci..

[3]  Edward P. Jaeger,et al.  Application of Genetic Algorithms to Combinatorial Synthesis: A Computational Approach to Lead Identification and Lead Optimization†,∇ , 1996 .

[4]  Ján Plesník,et al.  On the sum of all distances in a graph or digraph , 1984, J. Graph Theory.

[5]  Sung Jin Cho,et al.  Rational Combinatorial Library Design. 1. Focus-2D: A New Approach to the Design of Targeted Combinatorial Chemical Libraries , 1998, J. Chem. Inf. Comput. Sci..

[6]  S. P. Fodor,et al.  Applications of combinatorial technologies to drug discovery. 1. Background and peptide combinatorial libraries. , 1994, Journal of medicinal chemistry.

[7]  Darren V. S. Green,et al.  Selecting Combinatorial Libraries to Optimize Diversity and Physical Properties , 1999, J. Chem. Inf. Comput. Sci..

[8]  Robert P. Sheridan,et al.  Using a Genetic Algorithm To Suggest Combinatorial Libraries , 1995, J. Chem. Inf. Comput. Sci..

[9]  Irwin D. Kuntz,et al.  A fast and efficient method for 2D and 3D molecular shape description , 1992, J. Comput. Aided Mol. Des..

[10]  Yvonne C. Martin,et al.  Use of Structure-Activity Data To Compare Structure-Based Clustering Methods and Descriptors for Use in Compound Selection , 1996, J. Chem. Inf. Comput. Sci..

[11]  Ivan Gutman,et al.  A Collective Property of Trees and Chemical Trees , 1998, J. Chem. Inf. Comput. Sci..

[12]  P. Seybold,et al.  Molecular modeling of the physical properties of the alkanes , 1988 .

[13]  Venkat Venkatasubramanian,et al.  Evolutionary Design of Molecules with Desired Properties Using the Genetic Algorithm , 1995, J. Chem. Inf. Comput. Sci..

[14]  Andrew C. Good,et al.  Investigating the extension of pairwise distance pharmacophore measures to triplet-based descriptors , 1995, J. Comput. Aided Mol. Des..

[15]  J. Ellman,et al.  Combinatorial chemistry and new drugs. , 1997, Scientific American.

[16]  D. Rouvray.  The Search for Useful Topological Indices in Chemistry , 1973 .

[17]  Herbert S. Wilf.  The Uniform Selection of Free Trees , 1981, J. Algorithms.

[18]  Sung Jin Cho,et al.  Rational Combinatorial Library Design. 2. Rational Design of Targeted Combinatorial Peptide Libraries Using Chemical Similarity Probe and the Inverse QSAR Approaches , 1998, J. Chem. Inf. Comput. Sci..

[19]  Yvonne C. Martin,et al.  The Information Content of 2D and 3D Structural Descriptors Relevant to Ligand-Receptor Binding , 1997, J. Chem. Inf. Comput. Sci..