The Quest for Bioisosteric Replacements

To help advance drug discovery projects, a new and validated search method is presented by which potential bioisosteric replacements can be retrieved from a database of more than 700,000 structural fragments. The heart of the search method is an optimized topological pharmacophore fingerprint which describes each fragment as a combination of attachment points, hydrogen bond donors and acceptors, hydrophobic centers, conjugated atoms, and non-hydrogen atoms. In the fingerprint the influence of the attachment point is enhanced by giving it extra weight relative to the other descriptors. The Euclidean distance has proven to be the optimum distance measure to compare the fingerprints in a database search. The performance of the pharmacophore fingerprint based search method has been validated using more than 2200 bioisosteric fragment pairs extracted in an unbiased procedure from the BIOSTER database. The true bioisosteric pairs have been compared with pairs of random fragments originating from the WDI database. Normalized by the standard deviation of the random pairs distance distributions, an excellent separation of true pairs from random pairs was obtained for R-group fragments (2.2 standard deviation units) as well as for linkers (2.6 units) and cores (2.6 units). The bioisoster search method has been implemented as an intranet application called IBIS and is now routinely used by Organon researchers.

[1]  E. LaVoie,et al.  Bioisosterism: A Rational Approach in Drug Design , 1997 .

[2]  Peter Ertl,et al.  Cheminformatics Analysis of Organic Substituents: Identification of the Most Common Substituents, Calculation of Substituent Properties, and Automatic Identification of Drug‐Like Bioisosteric Groups. , 2003 .

[3]  L. M. Lima,et al.  Bioisosterism: a useful strategy for molecular modification and drug design. , 2005, Current medicinal chemistry.

[4]  Paul Watson,et al.  Calculating the knowledge-based similarity of functional groups using crystallographic data , 2001, J. Comput. Aided Mol. Des..

[5]  P. van Galen,et al.  1-Aminoisoquinoline as benzamidine isoster in the design and synthesis of orally active thrombin inhibitors. , 1999, Bioorganic & medicinal chemistry letters.

[6]  C. Thornber,et al.  Isosterism and molecular modification in drug design , 1979 .

[7]  P. Olesen,et al.  The use of bioisosteric groups in lead optimization. , 2001, Current opinion in drug discovery & development.

[8]  Johann Gasteiger,et al.  Hash codes for the identification and classification of molecular structure elements , 1994, J. Comput. Chem..

[9]  Bruno Giethlen,et al.  Molecular Variations Based on Isosteric Replacements , 2008 .

[10]  Robert P. Sheridan,et al.  The Most Common Chemical Replacements in Drug-Like Compounds , 2002, J. Chem. Inf. Comput. Sci..

[11]  P Willett,et al.  Grouping of coefficients for the calculation of inter-molecular similarity and dissimilarity using 2D fragment bit-strings. , 2002, Combinatorial chemistry & high throughput screening.

[12]  M. Hussain,et al.  Prodrugs to Improve the Oral Bioavailability of a Diacidic Nonpeptide Angiotensin II Antagonist , 1995, Pharmaceutical Research.

[13]  István Ujváry,et al.  Extended Summary: BIOSTER—a database of structurally analogous compounds , 1997 .

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

[15]  Hans Briem,et al.  Flexsim-R: A virtual affinity fingerprint descriptor to calculate similarities of functional groups , 2002, J. Comput. Aided Mol. Des..

[16]  Peter Gedeck,et al.  Calculation of Intersubstituent Similarity Using R-Group Descriptors , 2003, J. Chem. Inf. Comput. Sci..