Targeted molecular diversity in drug discovery: Integration of structure-based design and combinatorial chemistry

A powerful new approach emerging in drug discovery research combines computational screening of virtual combinatorial libraries against a therapeutic target and targeted combinatorial library synthesis. This new approach includes positive features from both structure-based design and combinatorial chemistry. It has the potential of producing combinatorial libraries with a high hit rate, and hence accelerates the generation of quality lead compounds. The effectiveness of this novel approach has been shown by the design and synthesis of potent inhibitors for serine and aspartyl proteases.

[1]  Hans-Joachim Böhm,et al.  The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure , 1994, J. Comput. Aided Mol. Des..

[2]  I D Kuntz,et al.  Structure-based design and combinatorial chemistry yield low nanomolar inhibitors of cathepsin D. , 1997, Chemistry & biology.

[3]  J. Mason,et al.  New perspectives in lead generation II: Evaluating molecular diversity , 1996 .

[4]  T. Carell,et al.  New promise in combinatorial chemistry: synthesis, characterization, and screening of small-molecule libraries in solution. , 1995, Chemistry & biology.

[5]  A. W. Czarnik,et al.  Combinatorial Organic Synthesis Using Parke-Davis's DIVERSOMER Method , 1996 .

[6]  Q. Zheng,et al.  Computational screening of combinatorial libraries via multicopy sampling , 1997 .

[7]  Klaus Gubernator,et al.  Optimization of the Biological Activity of Combinatorial Compound Libraries by a Genetic Algorithm , 1995 .

[8]  Mark A. Gallop,et al.  Combinatorial Organic Synthesis of Highly Functionalized Pyrrolidines: Identification of a Potent Angiotensin Converting Enzyme Inhibitor from a Mercaptoacyl Proline Library , 1995 .

[9]  W. Guida,et al.  The art and practice of structure‐based drug design: A molecular modeling perspective , 1996, Medicinal research reviews.

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

[11]  C. Zechel,et al.  Combinatorial Synthesis of Small Organic Molecules , 1996 .

[12]  David E. Clark,et al.  PRO_SELECT: Combining structure-based drug design and combinatorial chemistry for rapid lead discovery. 1. Technology , 1997, J. Comput. Aided Mol. Des..

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

[14]  P. Goodford.  A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. , 1985, Journal of medicinal chemistry.

[15]  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..

[16]  Discovery of a novel tetrahydroacridine acetylcholinesterase inhibitor through an indexed combinatorial library. , 1995, Chemistry & biology.

[17]  J. Spurlino,et al.  Serendipity meets precision: the integration of structure-based drug design and combinatorial chemistry for efficient drug discovery. , 1997, Structure.

[18]  Jonathan A. Ellman,et al.  Synthesis and Applications of Small Molecule Libraries. , 1996, Chemical reviews.

[19]  I. Kuntz,et al.  Using shape complementarity as an initial screen in designing ligands for a receptor binding site of known three-dimensional structure. , 1988, Journal of medicinal chemistry.

[20]  M. J. Gardner,et al.  COMBINATORIAL SYNTHESIS : THE DESIGN OF COMPOUND LIBRARIES AND THEIR APPLICATION TO DRUG DISCOVERY , 1995 .

[21]  I. Kuntz,et al.  Automated docking with grid‐based energy evaluation , 1992 .

[22]  I. Kuntz.  Structure-Based Strategies for Drug Design and Discovery , 1992, Science.

[23]  G. V. Paolini,et al.  Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes , 1997, J. Comput. Aided Mol. Des..

[24]  D. Banner,et al.  Crystallographic analysis at 3.0-A resolution of the binding to human thrombin of four active site-directed inhibitors. , 1994, The Journal of biological chemistry.

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

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

[27]  Hans-Joachim Böhm,et al.  The computer program LUDI: A new method for the de novo design of enzyme inhibitors , 1992, J. Comput. Aided Mol. Des..

[28]  D. Kempf,et al.  Synthetic chemical diversity: solid phase synthesis of libraries of C2 symmetric inhibitors of HIV protease containing diamino diol and diamino alcohol cores. , 1995, Journal of medicinal chemistry.

[29]  W. DeGrado,et al.  Complementarity of Combinatorial Chemistry and Structure-Based Ligand Design: Application to the Discovery of Novel Inhibitors of Matrix Metalloproteinases , 1996 .