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A very large diversity space of synthetically accessible compounds for use with drug design programs

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Abstract

We have constructed a very large virtual diversity space containing more than 1013 chemical compounds. The diversity space is built from about 400 combinatorial libraries, which have been expanded by choosing sizeable collections of suitable R-groups that can be attached to each link point of their scaffolds. These R-group collections have been created by selecting reagents that have drug-like properties from catalogs of available chemicals. As members of known combinatorial libraries, the compounds in the diversity space are in general synthetically accessible and useful as potential drug leads. Hence, the diversity space can be used as a vast source of compounds by a de novo drug design program. For example, we have used such a program to generate inhibitors of HIV integrase enzyme that exhibited activity in the micromolar range.

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References

  1. G. Schneider H.-J. Böhm (2002) Drug Discov. Today 7 64 Occurrence Handle1:CAS:528:DC%2BD38XktVOgsw%3D%3D Occurrence Handle11790605

    CAS  PubMed  Google Scholar 

  2. http://www.mdli.com/products/experiment/available_ chem_dir/index.jsp

  3. Y. Nishibata A. Itai (1991) Tetrahedron 41 8985 Occurrence Handle10.1016/S0040-4020(01)86503-0

    Article  Google Scholar 

  4. D.K. Gehlhaar K.E. Moerder D. Zichi C.J. Sherman R.C. Ogden S.T. Freer (1995) J. Med. Chem. 38 466 Occurrence Handle10.1021/jm00003a010 Occurrence Handle1:CAS:528:DyaK2MXjtF2rtbw%3D Occurrence Handle7853340

    Article  CAS  PubMed  Google Scholar 

  5. R. Wang Y. Gao L. Lai (2000) J. Mol. Model 6 498 Occurrence Handle10.1007/s0089400060498 Occurrence Handle1:CAS:528:DC%2BD3cXnvVemtLo%3D

    Article  CAS  Google Scholar 

  6. D.E. Clark D. Frenkel S.A. Levy J. Li C.W. Murray B. Robson B. Waszkowycz D.R. Westhead (1995) J. Comput.-Aided Mol. Design 9 13 Occurrence Handle10.1007/BF00117275 Occurrence Handle1:CAS:528:DyaK2MXktV2ru70%3D

    Article  CAS  Google Scholar 

  7. C.W. Murray D.E. Clark T.R. Auton M.A. Firth J. Li R.A. Sykes B. Waszkowycz D.R. Westhead S.C. Young (1997) J. Comput.-Aided Mol. Design 11 193 Occurrence Handle10.1023/A:1008094712424 Occurrence Handle1:CAS:528:DyaK2sXis1KjtLg%3D

    Article  CAS  Google Scholar 

  8. Y. Sun T.J.A. Ewing A.G. Skillman I.D. Kuntz (1998) J. Comput.-Aided Mol. Design 12 597 Occurrence Handle10.1023/A:1008036704754 Occurrence Handle1:CAS:528:DyaK1MXjslajsg%3D%3D

    Article  CAS  Google Scholar 

  9. A.R. Leach J. Bradshaw D.V.S. Green M.M. Hann J.J. Delany SuffixIII (1999) J. Chem. Inf. Comput. Sci. 39 1161 Occurrence Handle10.1021/ci9904259 Occurrence Handle1:CAS:528:DyaK1MXmvFWlu7s%3D Occurrence Handle10614028

    Article  CAS  PubMed  Google Scholar 

  10. E.J. Martin R.E. Critchlow (1999) J. Comb. Chem. 1 32 Occurrence Handle10.1021/cc9800024 Occurrence Handle1:CAS:528:DyaK1cXnvFGrurs%3D Occurrence Handle10746013

    Article  CAS  PubMed  Google Scholar 

  11. S. Shi Z. Peng J. Kostrowicki G. Paderes A. Kuki (2000) J. Mol. Graph. Model 18 478 Occurrence Handle10.1016/S1093-3263(00)00069-3 Occurrence Handle1:CAS:528:DC%2BD3cXotVOit7o%3D Occurrence Handle11143564

    Article  CAS  PubMed  Google Scholar 

  12. R.P. Sheridan S.G. SanFeliciano S.K. Kearsley (2000) J. Mol. Graph. Model 18 320 Occurrence Handle10.1016/S1093-3263(00)00060-7 Occurrence Handle1:CAS:528:DC%2BD3cXotVOisb8%3D Occurrence Handle11143552

    Article  CAS  PubMed  Google Scholar 

  13. V.S. Lobanov D.K. Agrafiotis (2002) Comb. Chem. High Throughput Screen 5 167 Occurrence Handle1:CAS:528:DC%2BD38Xjt1amsrg%3D Occurrence Handle11966425

    CAS  PubMed  Google Scholar 

  14. R.D. Cramer D.E. Patterson R.D. Clark F. Soltanshahi M.S. Lawless (1998) J. Chem. Inf. Comput. Sci. 38 1010 Occurrence Handle10.1021/ci9800209 Occurrence Handle1:CAS:528:DyaK1cXmtVGgtbg%3D

    Article  CAS  Google Scholar 

  15. E.K. Kick D.C. Roe A.G. Skillman G. Liu T.J.A. Ewing Y. Sun I.D. Kuntz J.A. Ellman (1997) Chem. Biol. 4 297 Occurrence Handle10.1016/S1074-5521(97)90073-9 Occurrence Handle1:CAS:528:DyaK2sXjs1ekt7s%3D Occurrence Handle9195867

    Article  CAS  PubMed  Google Scholar 

  16. S. Bräse S. Dahmen M. Pfefferkorn (2000) J. Comb. Chem. 2 710 Occurrence Handle10.1021/cc000051s Occurrence Handle11126299

    Article  PubMed  Google Scholar 

  17. R.E. Dolle K.H. Nelson SuffixJr. (1999) J. Comb. Chem. 1 235 Occurrence Handle10.1021/cc9900192 Occurrence Handle1:CAS:528:DyaK1MXktlantbw%3D Occurrence Handle10748736

    Article  CAS  PubMed  Google Scholar 

  18. R.E. Dolle (2000) J. Comb. Chem. 2 383 Occurrence Handle10.1021/cc000055x Occurrence Handle1:CAS:528:DC%2BD3cXmtlSjsrY%3D Occurrence Handle11029163

    Article  CAS  PubMed  Google Scholar 

  19. R.E. Dolle (2001) J. Comb. Chem. 3 477 Occurrence Handle10.1021/cc010049g Occurrence Handle1:CAS:528:DC%2BD3MXnt12qurk%3D Occurrence Handle11703143

    Article  CAS  PubMed  Google Scholar 

  20. R.E. Dolle (2002) J. Comb. Chem. 4 1 Occurrence Handle10.1021/cc020039v Occurrence Handle11790135

    Article  PubMed  Google Scholar 

  21. R.G. Franzen (2000) J. Comb. Chem. 2 195 Occurrence Handle10.1021/cc000002f Occurrence Handle1:CAS:528:DC%2BD3cXisVOqurY%3D Occurrence Handle10827923

    Article  CAS  PubMed  Google Scholar 

  22. G.R. Gustafson C.M. Baldino M.-M.E. O’Donnell A. Sheldon R.J. Tarsa C.J. Verni D.L. Coffen (1998) Tetrahedron 54 4051 Occurrence Handle10.1016/S0040-4020(98)00134-3 Occurrence Handle1:CAS:528:DyaK1cXitleru7s%3D

    Article  CAS  Google Scholar 

  23. Sigma-Aldrich Co., http://www.sigmaaldrich.com

  24. Acros Organics http://www.acros.be

  25. Lancaster Synthesis http://www.lancastersynthesis.com

  26. TCI Tokyo Kasei Kogyo Co., Ltd., http://www.tokyokasei.co.jp/catalogue/index.html

  27. J.R. Ullman (1976) J. Associat. Comp. Machinery 23 31

    Google Scholar 

  28. HyperChem(TM), Hypercube, Inc., Gainesville, Florida, USA, http://www.hyper.com

  29. A.L. Smith G.I. Stevenson C.J. Swain J.L. Castro (1998) Tetrahedron Lett. 39 8317 Occurrence Handle10.1016/S0040-4039(98)01824-3 Occurrence Handle1:CAS:528:DyaK1cXmvFSgsL0%3D

    Article  CAS  Google Scholar 

  30. C.A. Lipinski F. Lombardo B.W. Dominy P.J. Feeney (1997) Adv. Drug Deliv. Rev. 23 3 Occurrence Handle10.1016/S0169-409X(96)00423-1 Occurrence Handle1:CAS:528:DyaK2sXktlKlsQ%3D%3D

    Article  CAS  Google Scholar 

  31. T.S. Haque A.G. Skillman C.E. Lee H. Habashita I.Y. Gluzman T.J.A. Ewing D.E. Goldberg I.D. Kuntz J.A. Ellman (1999) J. Med. Chem. 42 1428 Occurrence Handle10.1021/jm980641t Occurrence Handle1:CAS:528:DyaK1MXitFSgsro%3D Occurrence Handle10212129

    Article  CAS  PubMed  Google Scholar 

  32. C. Kallus T. Opatz T. Wunberg W. Schmidt S. Henke H. Kunz (1999) Tetrahedron Lett. 40 7783 Occurrence Handle10.1016/S0040-4039(99)01690-1 Occurrence Handle1:CAS:528:DyaK1MXmslaitL4%3D

    Article  CAS  Google Scholar 

  33. MDL Drug Data Report (MDDR), http://www.mdli.com

  34. A.E. Muryshev D.N. Tarasov A.V. Butygin O.Yu. Butygina A.B. Aleksandrov S.M. Nikitin (2003) J. Comput.-Aided Mol. Design 17 597 Occurrence Handle10.1023/B:JCAM.0000005766.95985.7e Occurrence Handle1:CAS:528:DC%2BD3sXptlGltbk%3D

    Article  CAS  Google Scholar 

  35. P. Willett J.M. Barnard G.M. Downs (1998) J. Chem. Inf. Comput. Sci., 38 983

    Google Scholar 

  36. Clark R.D. (2001). In Ghose A.K., Viswanadhan V.N. (Eds.), Combinatorial Library Design and Evaluation, Marcel Dekker, Inc., New York, pp. 337–362

  37. Gillet V.J., Willett P. (2001). In Ghose A.K. and Viswanadhan V.N. (Eds.), Combinatorial Library Design and Evaluation, Marcel Dekker, Inc., New York, pp. 379–398

  38. K. Sayasith G. Sauve J. Yelle (2001) Exp. Opin. Ther. Targets 5 444

    Google Scholar 

  39. F. Zouhiri J-F. Mouscadet K. Mekouar D. Desmaële D. Savoure H. Leh F. Subra M. Le Bret C. Auclair J. d’Angelo (2000) J. Med. Chem. 43 1533 Occurrence Handle10.1021/jm990467o Occurrence Handle1:CAS:528:DC%2BD3cXhvVGitro%3D Occurrence Handle10780910

    Article  CAS  PubMed  Google Scholar 

  40. M.S. South T.A. Dice J.J. Parlow (2000) Biotechnol. Bioeng. 71 51 Occurrence Handle10.1002/(SICI)1097-0290(200024)71:1<51::AID-BIT8>3.0.CO;2-O Occurrence Handle1:CAS:528:DC%2BD3cXpvVSjtA%3D%3D Occurrence Handle10629536

    Article  CAS  PubMed  Google Scholar 

  41. E. Verner B.A. Katz J.R. Spencer D. Allen J. Hataye W. Hruzewicz H.C. Hui A. Kolesnikov Y. Li C. Luong A. Martelli K. Radika R. Rai M. She W. Shrader P.A. Sprengeler S. Trapp J. Wang W.B. Young R.L. Mackman (2001) J. Med. Chem. 44 2753 Occurrence Handle10.1021/jm0100638 Occurrence Handle1:CAS:528:DC%2BD3MXltVSitrw%3D Occurrence Handle11495587

    Article  CAS  PubMed  Google Scholar 

  42. J.L. Silen A.T. Lu D.W. Solas M.A. Gore D. Maclean N.H. Shah J.M. Ciffin N.S. Bhinderwala Y. Wang K.T. Tsutsui G.C. Look D.A. Campbell R.L. Hale M. Navre C.R. DeLuca-Flaherty (1998) Antimicrob. Agents Chemother. 42 1447 Occurrence Handle1:STN:280:DyaK1c3oslGrug%3D%3D Occurrence Handle9624492

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Algodign LLC, Bolshaya Sadovaya 8, Moscow, 103001, Russia

    Sergey Nikitin, Natalia Zaitseva, Olga Demina, Vera Solovieva, Evgeny Mazin, Sergey Mikhalev, Maxim Smolov, Anatoly Rubinov, Peter Vlasov, Dmitry Lepikhin, Denis Khachko, Cary Queen & Viktor Zosimov

  2. Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA, 92037, USA

    Valery Fokin

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  1. Sergey Nikitin
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Correspondence to Sergey Nikitin.

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Nikitin, S., Zaitseva, N., Demina, O. et al. A very large diversity space of synthetically accessible compounds for use with drug design programs. J Comput Aided Mol Des 19, 47–63 (2005). https://doi.org/10.1007/s10822-005-0097-6

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