Minor Groove Binders and Drugs Targeting Proteins Cover Complementary Regions in Chemical Shape Space

DNA minor groove binders (MGBs) are known to influence gene expression and are therefore widely studied to explore their therapeutic potential. We identified shape-based virtual screening with ROCS as a highly effective computational approach to enrich known MGBs in top-ranked molecules. Discovery of ten previously unknown MGBs by shape-based screening further confirmed the relevance of ligand shape for minor groove affinity. Based on experimental testing we propose three simple rules (at least two positive charges, four nitrogen atoms, and one aromatic ring) as filters to reach even better enrichment of true positives in ROCS hit lists. Interestingly, shape-based ranking of MGBs versus FDA-approved drugs again leads to high enrichment rates, indicating complementary coverage of chemical shape space and indicating minor groove affinity to be unfavorable for approval of drugs targeting proteins.

[1]  A. Kamal,et al.  DNA binding potential and cytotoxicity of newly designed pyrrolobenzodiazepine dimers linked through a piperazine side-armed-alkane spacer. , 2006, Bioorganic & medicinal chemistry.

[2]  J. Phillips,et al.  Cyclic pyrrole-imidazole polyamides targeted to the androgen response element. , 2009, Journal of the American Chemical Society.

[3]  S Neidle,et al.  DNA minor-groove recognition by small molecules. , 2001, Natural product reports.

[4]  J. Pin,et al.  Virtual screening workflow development guided by the "receiver operating characteristic" curve approach. Application to high-throughput docking on metabotropic glutamate receptor subtype 4. , 2005, Journal of medicinal chemistry.

[5]  P. Dervan,et al.  Modulating hypoxia-inducible transcription by disrupting the HIF-1-DNA interface. , 2007, ACS chemical biology.

[6]  Thierry Langer,et al.  Fast and Efficient in Silico 3D Screening: Toward Maximum Computational Efficiency of Pharmacophore-Based and Shape-Based Approaches , 2007, J. Chem. Inf. Model..

[7]  R. Sakai,et al.  Bioactive compounds from aquatic and terrestrial sources. , 1990, Journal of natural products.

[8]  Hans-Dieter Arndt,et al.  Minimization of a protein-DNA dimerizer. , 2007, Journal of the American Chemical Society.

[9]  P. Peixoto,et al.  Unusually strong binding to the DNA minor groove by a highly twisted benzimidazole diphenylether: induced fit and bound water. , 2007, Biochemistry.

[10]  G. Parkinson,et al.  Targeting the DNA minor groove with fused ring dicationic compounds: comparison of in silico screening and a high-resolution crystal structure. , 2006, Bioorganic & medicinal chemistry letters.

[11]  F. C. Goble.  Chemotherapy of experimental trypanosomiasis; trypanocidal activity of certain bis (2-methyl-4-amino-6-quinolyl) amides and ethers. , 1950, The Journal of pharmacology and experimental therapeutics.

[12]  Klaus R. Liedl,et al.  DNA Minor Groove Pharmacophores Describing Sequence Specific Properties , 2007, J. Chem. Inf. Model..

[13]  D. Boger,et al.  Assessment of solution-phase positional scanning libraries based on distamycin A for the discovery of new DNA binding agents. , 2000, Bioorganic & medicinal chemistry.

[14]  S Neidle,et al.  A crystallographic and spectroscopic study of the complex between d(CGCGAATTCGCG)2 and 2,5-bis(4-guanylphenyl)furan, an analogue of berenil. Structural origins of enhanced DNA-binding affinity. , 1995, Biochemistry.

[15]  M. Rots,et al.  Therapeutic modulation of endogenous gene function by agents with designed DNA-sequence specificities. , 2003, Nucleic acids research.

[16]  Brian K. Shoichet,et al.  ZINC - A Free Database of Commercially Available Compounds for Virtual Screening , 2005, J. Chem. Inf. Model..

[17]  M. Georgiadis,et al.  A high-throughput, high-resolution strategy for the study of site-selective DNA binding agents: analysis of a "highly twisted" benzimidazole-diamidine. , 2006, Journal of the American Chemical Society.

[18]  Peter B. Dervan,et al.  Regulation of gene expression by small molecules , 1997, Nature.

[19]  R. Mann,et al.  The role of DNA shape in protein-DNA recognition , 2009, Nature.

[20]  P. Peixoto,et al.  Direct inhibition of the DNA-binding activity of POU transcription factors Pit-1 and Brn-3 by selective binding of a phenyl-furan-benzimidazole dication , 2008, Nucleic acids research.

[21]  Michael Hedrick,et al.  Total Synthesis of Distamycin A and 2640 Analogues: A Solution-Phase Combinatorial Approach to the Discovery of New, Bioactive DNA Binding Agents and Development of a Rapid, High-Throughput Screen for Determining Relative DNA Binding Affinity or DNA Binding Sequence Selectivity , 2000 .

[22]  G. Parkinson,et al.  A new class of symmetric bisbenzimidazole-based DNA minor groove-binding agents showing antitumor activity. , 2001, Journal of medicinal chemistry.

[23]  J F Brandts,et al.  Rapid measurement of binding constants and heats of binding using a new titration calorimeter. , 1989, Analytical biochemistry.

[24]  D. Case,et al.  NMR structure of a cyclic polyamide-DNA complex. , 2004, Journal of the American Chemical Society.

[25]  R. Mann,et al.  Origins of specificity in protein-DNA recognition. , 2010, Annual review of biochemistry.

[26]  A. Rich,et al.  Molecular structure of the A-tract DNA dodecamer d(CGCAAATTTGCG) complexed with the minor groove binding drug netropsin. , 1993, Biochemistry.

[27]  Simona Distinto,et al.  Evaluation of the performance of 3D virtual screening protocols: RMSD comparisons, enrichment assessments, and decoy selection—What can we learn from earlier mistakes? , 2008, J. Comput. Aided Mol. Des..

[28]  C. Suckling.  Minor groove binders 1998 – 2004 , 2004 .

[29]  E. De Clercq,et al.  Antifungal and antibacterial activities of diarylamidine derivatives , 1980, Antimicrobial Agents and Chemotherapy.

[30]  Uli Schmitz,et al.  Minor groove DNA binders as antimicrobial agents. 1. Pyrrole tetraamides are potent antibacterials against vancomycin resistant Enterococci [corrected] and methicillin resistant Staphylococcus aureus. , 2002, Journal of medicinal chemistry.

[31]  Philip M. Dean,et al.  Three-dimensional hydrogen-bond geometry and probability information from a crystal survey , 1996, J. Comput. Aided Mol. Des..

[32]  Alexander D. MacKerell,et al.  Consideration of Molecular Weight during Compound Selection in Virtual Target-Based Database Screening , 2003, J. Chem. Inf. Comput. Sci..

[33]  M. Searle,et al.  DNA minor groove recognition by bis-benzimidazole analogues of Hoechst 33258: insights into structure-DNA affinity relationships assessed by fluorescence titration measurements. , 1999, Nucleic acids research.

[34]  Joel H. Hildebrand,et al.  A Spectrophotometric Investigation of the Interaction of Iodine with Aromatic Hydrocarbons , 1949 .

[35]  Yuchun Wang,et al.  The interaction of human serum albumin with a novel antidiabetic agent--SU-118. , 2004, Journal of pharmaceutical sciences.

[36]  J. J. Stephanos.  Drug-protein interactions: two-site binding of heterocyclic ligands to a monomeric hemoglobin. , 1996, Journal of inorganic biochemistry.

[37]  Michal Vieth,et al.  Lessons in Molecular Recognition, 2. Assessing and Improving Cross-Docking Accuracy , 2007, J. Chem. Inf. Model..

[38]  Klaus R. Liedl,et al.  Hydrogen-Bonding Patterns of Minor Groove-Binder-DNA Complexes Reveal Criteria for Discovery of New Scaffolds , 2009, J. Chem. Inf. Model..

[39]  A. Rich,et al.  Binding of a Hoechst dye to d(CGCGATATCGCG) and its influence on the conformation of the DNA fragment. , 1989, Biochemistry.

[40]  J. A. Grant,et al.  A shape-based 3-D scaffold hopping method and its application to a bacterial protein-protein interaction. , 2005, Journal of medicinal chemistry.

[41]  P. Labute.  A widely applicable set of descriptors. , 2000, Journal of molecular graphics & modelling.

[42]  D. Boykin,et al.  Accumulation and Intracellular Distribution of Antitrypanosomal Diamidine Compounds DB75 and DB820 in African Trypanosomes , 2006, Antimicrobial Agents and Chemotherapy.

[43]  R. Nagem,et al.  Structural binding evidence of the trypanocidal drugs berenil and pentacarinate active principles to a serine protease model. , 2010, International journal of biological macromolecules.

[44]  G. Narahari Sastry,et al.  Comparison of Computational Methods to Model DNA Minor Groove Binders , 2011, J. Chem. Inf. Model..

[45]  T. Haran,et al.  The unique structure of A-tracts and intrinsic DNA bending , 2009, Quarterly Reviews of Biophysics.

[46]  S. Vooturi,et al.  Design, synthesis, and structure-activity relationships of benzophenone-based tetraamides as novel antibacterial agents. , 2009, Journal of medicinal chemistry.

[47]  P. Dervan,et al.  Programmable DNA binding oligomers for control of transcription. , 2005, Current medicinal chemistry. Anti-cancer agents.

[48]  Stephen Neidle,et al.  Virtual screening of DNA minor groove binders. , 2006, Journal of medicinal chemistry.

[49]  Michael P Barrett,et al.  Pentamidine uptake and resistance in pathogenic protozoa: past, present and future. , 2003, Trends in parasitology.

[50]  D. Boger,et al.  Discovery of inhibitors of aberrant gene transcription from Libraries of DNA binding molecules: inhibition of LEF-1-mediated gene transcription and oncogenic transformation. , 2009, Journal of the American Chemical Society.

[51]  Christian Melander,et al.  Regulation of gene expression with pyrrole-imidazole polyamides. , 2004, Journal of biotechnology.

[52]  B. Ramakrishnan,et al.  Crystal structures of the side-by-side binding of distamycin to AT-containing DNA octamers d(ICITACIC) and d(ICATATIC). , 1997, Journal of molecular biology.

[53]  Jean-Jacques Helesbeux,et al.  Antimicrobial lexitropsins containing amide, amidine, and alkene linking groups. , 2007, Journal of medicinal chemistry.

[54]  S. Neidle,et al.  Symmetric bis-benzimidazoles: new sequence-selective DNA-binding molecules , 1999 .

[55]  Simona Distinto,et al.  How To Optimize Shape-Based Virtual Screening: Choosing the Right Query and Including Chemical Information , 2009, J. Chem. Inf. Model..

[56]  J. Šponer,et al.  Crystal structure of d(GGCCAATTGG) complexed with DAPI reveals novel binding mode. , 1999, Biochemistry.

[57]  Luc Van Meervelt,et al.  Two 1 : 1 binding modes for distamycin in the minor groove of d(GGCCAATTGG). , 2002, European journal of biochemistry.

[58]  J. Lah,et al.  Energetic diversity of DNA minor-groove recognition by small molecules displayed through some model ligand-DNA systems. , 2004, Journal of molecular biology.

[59]  Remo Rohs,et al.  Molecular flexibility in ab initio drug docking to DNA: binding-site and binding-mode transitions in all-atom Monte Carlo simulations , 2005, Nucleic acids research.

[60]  J. Lown,,et al.  Synthetic DNA minor groove-binding drugs. , 1999, Pharmacology & therapeutics.

[61]  Diana C. Roe,et al.  Finding potential DNA-binding compounds by using molecular shape , 1994, J. Comput. Aided Mol. Des..