Molecular diversity in the context of leadlikeness: compound properties that enable effective biochemical screening.

Molecular diversity is of vital importance in drug screening in general and for the discovery and development of new pharmacophores in particular. Biochemical screening is a powerful tool for pharmacophore development given understanding of the properties of a good lead compound operating in the biochemical environment. The properties of leadlikeness have evolved to accommodate the artificial conditions of a biochemical assay. Accordingly, the properties of leadlikeness that are suited for screening at protein targets biochemically are different and complementary to the properties of druglikeness used to guide the selection of good compounds studied biologically in cellular studies and animal models. The benefits of leadlikeness in the biochemical screening arena (including fragment-based screening and co-crystallization studies) are described here and recommendations are forwarded for the generation of leadlike molecular diversity. Chemically stable low molecular weight 'minimalist' compounds (or fragments) with dense heteroatom substitution and variable conformational constraint are promoted as conceptually superior compounds for biochemical screening.

[1]  J. C. Hodges,et al.  Polymer-Supported Quenching Reagents for Parallel Purification , 1997 .

[2]  John Davies,et al.  Design of small molecule libraries for NMR screening and other applications in drug discovery. , 2002, Current topics in medicinal chemistry.

[3]  B. Shoichet.  Screening in a spirit haunted world. , 2006, Drug discovery today.

[4]  Paul A Tempest,et al.  Recent advances in heterocycle generation using the efficient Ugi multiple-component condensation reaction. , 2005, Current opinion in drug discovery & development.

[5]  J. Mittendorf,et al.  Enantioselective synthesis of 2,3-diamino acids by the bislactim ether method , 1991 .

[6]  K. Sharpless,et al.  A New Approach to Osmium‐Catalyzed Asymmetric Dihydroxylation and Aminohydroxylation of Olefins , 2002 .

[7]  B. Shoichet,et al.  Identification and prediction of promiscuous aggregating inhibitors among known drugs. , 2003, Journal of medicinal chemistry.

[8]  B. Shoichet,et al.  A specific mechanism of nonspecific inhibition. , 2003, Journal of medicinal chemistry.

[9]  J. C. Hodges,et al.  Polymer‐Supported Quenching Reagents for Parallel Purification. , 1997 .

[10]  Edgar Jacoby,et al.  Library design for fragment based screening. , 2005, Current topics in medicinal chemistry.

[11]  P. Hajduk,et al.  SAR by NMR: An Analysis of Potency Gains Realized Through Fragment‐linking and Fragment‐elaboration Strategies for Lead Generation , 2006 .

[12]  T. Insel,et al.  NIH Molecular Libraries Initiative , 2004, Science.

[13]  G. Bemis,et al.  A minimalist approach to fragment‐based ligand design using common rings and linkers: Application to kinase inhibitors , 2004, Proteins.

[14]  Tudor I. Oprea,et al.  Pursuing the leadlikeness concept in pharmaceutical research. , 2004, Current opinion in chemical biology.

[15]  Andrew R. Leach,et al.  Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery , 2001, J. Chem. Inf. Comput. Sci..

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

[17]  Brian K Shoichet,et al.  Kinase inhibitors: not just for kinases anymore. , 2003, Journal of medicinal chemistry.

[18]  B. Kedrowski.  Synthesis of orthogonally protected (R)- and (S)-2-methylcysteine via an enzymatic desymmeterization and Curtius rearrangement. , 2003, The Journal of organic chemistry.

[19]  Jeremy N. Burrows,et al.  4.18 – Lead Discovery and the Concepts of Complexity and Lead-Likeness in the Evolution of Drug Candidates , 2007 .

[20]  P. Hajduk,et al.  SAR by NMR: putting the pieces together. , 2006, Molecular interventions.

[21]  D. Fattori,et al.  Fragment-based drug design: combining philosophy with technology. , 2007, Current opinion in drug discovery & development.

[22]  Stephen R. Johnson,et al.  Molecular properties that influence the oral bioavailability of drug candidates. , 2002, Journal of medicinal chemistry.

[23]  G. Rishton.  Nonleadlikeness and leadlikeness in biochemical screening. , 2003, Drug discovery today.

[24]  Miles G. Siegel,et al.  Use of solid supported nucleophiles and electrophiles for the purification of non-peptide small molecule libraries , 1996 .

[25]  Donna M. Huryn,et al.  Chapter 26 The Molecular Libraries Screening Center Network (MLSCN): Identifying Chemical Probes of Biological Systems , 2007, Annual Reports in Medicinal Chemistry.

[26]  P. Hajduk,et al.  A decade of fragment-based drug design: strategic advances and lessons learned , 2007, Nature Reviews Drug Discovery.

[27]  Renaldo Mendoza,et al.  ALARM NMR: a rapid and robust experimental method to detect reactive false positives in biochemical screens. , 2005, Journal of the American Chemical Society.

[28]  S. Hitchcock,et al.  Structure-brain exposure relationships. , 2006, Journal of medicinal chemistry.

[29]  G. Rishton.  Reactive compounds and in vitro false positives in HTS , 1997 .

[30]  Dan C. Fara,et al.  Lead-like, drug-like or “Pub-like”: how different are they? , 2007, J. Comput. Aided Mol. Des..

[31]  Kerim Babaoglu,et al.  Deconstructing fragment-based inhibitor discovery , 2006, Nature chemical biology.

[32]  Tudor I. Oprea,et al.  The Design of Leadlike Combinatorial Libraries. , 1999, Angewandte Chemie.

[33]  H. Verheij,et al.  Leadlikeness and structural diversity of synthetic screening libraries , 2006, Molecular Diversity.

[34]  C. Hulme,et al.  "Multi-component reactions : emerging chemistry in drug discovery" 'from xylocain to crixivan'. , 2003, Current medicinal chemistry.

[35]  Daniel F. Wyss and Hugh L. Eaton.  Fragment-Based Approaches to Lead Discovery , 2007 .

[36]  Wolfgang Guba,et al.  Development of a virtual screening method for identification of "frequent hitters" in compound libraries. , 2002, Journal of medicinal chemistry.

[37]  M. Uesugi,et al.  [Discovering high-affinity ligands for proteins: SAR by NMR]. , 2007, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[38]  S. Danishefsky,et al.  Small molecule natural products in the discovery of therapeutic agents: the synthesis connection. , 2006, The Journal of organic chemistry.

[39]  P. A. Magriotis,et al.  Efficient enantioselective synthesis of orthogonally protected (R)-α-alkylserines compatible with the solid phase peptide synthesis , 2006 .

[40]  Christopher P Austin,et al.  A high-throughput screen for aggregation-based inhibition in a large compound library. , 2007, Journal of medicinal chemistry.

[41]  Kristen B. LaBonte,et al.  Computational approaches to the prediction of blood-brain barrier permeability: A comparative analysis of central nervous system drugs versus secretase inhibitors for Alzheimer's disease. , 2006, Current opinion in drug discovery & development.

[42]  Alban Arrault,et al.  Managing, profiling and analyzing a library of 2.6 million compounds gathered from 32 chemical providers , 2006, Molecular Diversity.

[43]  Brian K Shoichet,et al.  Synergy and antagonism of promiscuous inhibition in multiple-compound mixtures. , 2006, Journal of medicinal chemistry.

[44]  Tudor I. Oprea,et al.  Is There a Difference Between Leads and Drugs? A Historical Perspective. , 2001 .

[45]  Alexander Dömling,et al.  Recent developments in isocyanide based multicomponent reactions in applied chemistry. , 2006, Chemical reviews.