Applications of the common software and methods of <i>denovo</i> drug design in the antitumor drug design

YIN Li; CHEN Linxi

doi:10.3969/j.issn.1006-0111.2014.01.003

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Article Navigation > Journal of Pharmaceutical Practice and Service > 2014 > 32(1): 9-15,34

YIN Li, CHEN Linxi. Applications of the common software and methods of denovo drug design in the antitumor drug design[J]. Journal of Pharmaceutical Practice and Service, 2014, 32(1): 9-15,34. doi: 10.3969/j.issn.1006-0111.2014.01.003

Citation:

YIN Li, CHEN Linxi. Applications of the common software and methods of denovo drug design in the antitumor drug design[J]. Journal of Pharmaceutical Practice and Service, 2014, 32(1): 9-15,34. doi: 10.3969/j.issn.1006-0111.2014.01.003

Applications of the common software and methods of denovo drug design in the antitumor drug design

doi: 10.3969/j.issn.1006-0111.2014.01.003

YIN Li,
CHEN Linxi

Institute of Pharmacy and Pharmacology, University of South China, Hunan Hengyang 421001, China

Received Date: 2013-02-21
Rev Recd Date: 2013-09-06

Abstract

Computer aided drug design had become part of the drug discovery process, greatly improved the speed of drug development compared with traditional drug finding methods. In particular, the de novo drug design method could be used to identify ligands with novel structure for a special target. Through computer simulation, researchers could find new ideas about how to change a compound to improve the drug properties or how to assemble some fragments to generate candidates which be drug-like, synthetically accessible and high affinity for a target. The common software of de novo design included LUDI, MCSS, LigBuilder, SPROUT, SYNOPSIS, BREED, LeapFrog and RACHEL, etc. The methods were fragments link and grow, side chain replacement, parent molecule evolve, template, scaffold hopping and so on. Discovery and development of cancer drugs had been revolutionized over the last decade. De novo drug design methods had already played a significant role in the discovery of some anticancer compounds such as kinesin spindle protein inhibitors, vascular endothelial growth factor inhibitors, cyclophilin A inhibitors, cell division cycle protein CDC25 inhibitors and BRAF inhibitors. The common software and methods of de novo drug design were summarized in this review and their applications in antitumor drug design were discussed.
- de novo drug design,
- antitumor drug,
- LUDI,
- LigBuilder,
- LeapFrog

References

[1]	Hoelder S, Clarke PA, Workman P. Discovery of small molecule cancer drugs:successes, challenges and opportunities[J]. Mol Oncol, 2012, 6 (2):155-176.
[2]	Kalyaanamoorthy S, Phoebe Chen Y-P. Structure-based drug design to augment hit discovery[J]. Drug Discov Today, 2011, 16(17-18):831-839.
[3]	Kutchukian PS, Shakhnovich EI. De novo design:balancing novelty and confined chemical space[J]. Expert Opin Drug Discov, 2010. 5(8), 789-812.
[4]	Park H, Jeong Y, Hong S. Structure-based de novo design and biochemical evaluation of novel BRAF kinase inhibitors[J]. Bioorg Med Chem Lett, 2012, 22(2):1027-1030.
[5]	Schneider G, Fechner U. Computer-based de novo design of drug-like molecules[J]. Nat Rev Drug Discov 2005, 4 (8):694-663.
[6]	Lipinski,C, Hopkins A. Navigating chemical space for biology and medicine[J]. Nature, 2004,432(7019):855-861.
[7]	Platania CB, Salomone S, Leggio GM, et al. Homology modeling of dopamine d(2) and d(3) receptors:molecular dynamics refinement and docking evaluation[J]. PloS One, 2012, 7 (9):44316.
[8]	Keseru GM, Makara GM. Hit discovery and hit-to-lead approaches[J]. Drug Discov Today, 2006, 11(15-16), 741-748.
[9]	Bohm HJ. The computer program LUDI:a new method for de novo design of enzyme inhibitors[J]. J Comput Aided Mol Des, 1992, 6 (1):61-78.
[10]	Wang RX, Gao Y, Lai LH. LigBuilder:a multi-purpose progrom for structure-based drug design[J]. J Mol Model, 2000, 6 (7-8); 498-516.
[11]	Wang RX, Liu L, Lai LH, et al. SCORE:A new empirical method for estimating the binding affinity of a protein-ligand complex[J]. J Mol Model, 1998, 4 (12):370-394.
[12]	Yuan,YX, Pei JF, Lai LH. LigBuilder 2:a practical de novo drug design approach[J]. J Chem Inform Model, 2011, 51 (5):1083-1091.
[13]	Cramer RD. Design and preliminary results of LeapFrog, a second generation de novo drug discovery tool[J]. J Mol Graphics, 1993, 11(4); 271-272.
[14]	Ambure PS, Gangwal RP, Sanganwar AT. 3D-QSAR and molecular docking analysis of biphenyl amide derivatives as p38α mitogen-activated protein kinase inhibitors[J]. Mol Divers, 2012,16(2):377-388.
[15]	Makhija MT, Kasliwal RT, Kulkarni VM, et al. De novo design and synthesis of HIV-1 integrase inhibitors[J]. Bioorg Med Chem, 2004, 12(9):2317-2333.
[16]	Schinerider G, Neidhart W, Giller T, et al. Scaffold-Hopping by topological search:a contribution to virtual screening[J]. Angewandte Chemie (International Ed. in English), Angew Chem Int Ed Engl, 1999, 38(19):2894-2896.
[17]	Schneider G. De novo design-hopping against hope[EB/OL]. Drug Discovery Today:Technologies.(2012-06-20)[2013-01-02].
[18]	Wolber G. 3D pharmacophore elucidation and virtual screening[J]. Drug Discov Today, 2010, 7(4):203-204.
[19]	Lauri G, Bartlett PA. CAVEAT:a program to facilitate the design of organic molecules[J]. J Comput Aided Mol Des, 1994, 8(1):51-66.
[20]	Beno BR, Langley DR. MORPH:a new tool for ligand design[J]. J Chem Inform Model, 2010, 50(6):1159-1164.
[21]	Maass P, Schulz-Gasch T, Stahl M, et al. Recore:a fast and versatile method for scaffold hopping based on small molecule crystal structure conformations[J]. J Chem Inform Model, 2007,47(2):390-399.
[22]	Gillet VJ, Newell W, Mata P, et al. SPROUT:recent developments in the de novo design of molecules[J]. J Chem Inform Comput Sci, 1994, 34:207-217.
[23]	Vinkers HM, de Jonge MR, Daeyaert FF, et al. SYNOPSIS:SYNthesize and optimize system in silico[J]. J Med Chem, 2003, 46:2765-2773.
[24]	Pierce AC, Rao G, Bemis GW, et al. BREED generating novel inhibitors through hybridization of known ligands. Aplication to CDK2, p38and HIV protease[J]. J Med Chem, 2004, 47:2768-2775.
[25]	Marra E, Palombo F, Ciliberto G, et al. Intratumoral electro-transfer of small interfering RNA against kinesin spindle protein (KSP) slows down tumor progression[J]. J Cell Physiol, 2013,228(1),58-64.
[26]	Jiang,C, Yang L, Wu WT, et al. De novo design, synthesis and biological evaluation of 1,4-dihydroquinolin-4-ones and 1,2,3,4-tetrahydroquinazolin-4-ones as potent kinesin spindle protein (KSP) inhibitors[J]. Bioorg Med Chem, 2011,19 (18):5612-5627.
[27]	Kim LA, D'Amore PA. A brief history of anti-VEGF for the treatment of ocular angiogenesis[J]. Am J Pathol, 2012, 181(2):376-379.
[28]	Uno M, Ban HS, Nabeyama W, et al. De novo design and synthesis of N-benzylanilines as new candidates for VEGFR tyrosine kinase inhibitors[J]. Org Biomol Chem, 2008, 6 (6):979-981.
[29]	Albert H, Santos S, Battaqlia E, et al. Differential expression of CDC25 phosphatases splice variants in human breast cancer cells[J]. Clin Chem Lab Med, 2011, 49(10):1707-1714.
[30]	Park H, Bahn YJ, Ryu SE, Structure-based de novo design and biochemical evaluation of novel Cdc25 phosphatase inhibitors[J]. Bioorg Med Chem Lett, 2009, 19(15):4330-4334.
[31]	Zhou DJ, Mei Q, Li JT, et al, Cyclophilin A and viral infections[J]. Bioch Biophys Res Comm, 2012,424(4), 647-650.
[32]	Choi KJ, Piao YJ, Lim MJ, et al. Overexpressed cyclophilin A in cancer cells renders resistance to hypoxia-and cisplatin-induced cell death[J]. Cancer Res, 2007, 67(8):3654-3662.
[33]	Ni SS, Yuan YX, Huang J, et al. Discovering potent small molecule inhibitors of cyclophilin A using de novo drug design approach[J]. J Med Chem, 2009, 52(17):5295-5298.
[34]	Wong C, Chen S. The development,application and limitations of breast cancer cell lines to study tamoxifen and aromataes inhibitor resistance[J]. J Steroid Biochem Mol Biol, 2012, 131(3-5):83-92.
[35]	Gueto C, Torres J, Vivas-Reyes R. CoMFA, LeapFrog and blind docking studies on sulfonanilide derivatives acting as selective aromatase expression regulators[J]. Eur J Med Chem, 2009, 44(9):3445-3451.
[36]	Su B, Diaz-Cruz ES, Landini S, et al. Novel sulfonanilide analoguew suppress aromataes expression and activity in breast cancer cells independent of COX-2 inhibiton[J]. J Med Chem, 2006, 49(4):1413-1419.
[37]	Davies H, Bignell GR, Cox C, et al. Mutations of the B-raf gene in human cancer[J]. Nature, 2002, 417(6892), 949-954.
[38]	Gopalsamy A, Shi M, Hu Y, et al. B-raf kinase inhibitors:hit enrichment through scaffold hopping[J]. Bioorg Med Chem Lett, 2010, 20(8):2431-2434.

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通讯作者: 陈斌, bchen63@163.com

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沈阳化工大学材料科学与工程学院沈阳 110142

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Applications of the common software and methods of denovo drug design in the antitumor drug design

Institute of Pharmacy and Pharmacology, University of South China, Hunan Hengyang 421001, China

Received Date: 2013-02-21

Rev Recd Date: 2013-09-06

Key words:

Abstract: Computer aided drug design had become part of the drug discovery process, greatly improved the speed of drug development compared with traditional drug finding methods. In particular, the de novo drug design method could be used to identify ligands with novel structure for a special target. Through computer simulation, researchers could find new ideas about how to change a compound to improve the drug properties or how to assemble some fragments to generate candidates which be drug-like, synthetically accessible and high affinity for a target. The common software of de novo design included LUDI, MCSS, LigBuilder, SPROUT, SYNOPSIS, BREED, LeapFrog and RACHEL, etc. The methods were fragments link and grow, side chain replacement, parent molecule evolve, template, scaffold hopping and so on. Discovery and development of cancer drugs had been revolutionized over the last decade. De novo drug design methods had already played a significant role in the discovery of some anticancer compounds such as kinesin spindle protein inhibitors, vascular endothelial growth factor inhibitors, cyclophilin A inhibitors, cell division cycle protein CDC25 inhibitors and BRAF inhibitors. The common software and methods of de novo drug design were summarized in this review and their applications in antitumor drug design were discussed.

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Reference (38)

[1]	Hoelder S, Clarke PA, Workman P. Discovery of small molecule cancer drugs:successes, challenges and opportunities[J]. Mol Oncol, 2012, 6 (2):155-176.
[2]	Kalyaanamoorthy S, Phoebe Chen Y-P. Structure-based drug design to augment hit discovery[J]. Drug Discov Today, 2011, 16(17-18):831-839.
[3]	Kutchukian PS, Shakhnovich EI. De novo design:balancing novelty and confined chemical space[J]. Expert Opin Drug Discov, 2010. 5(8), 789-812.
[4]	Park H, Jeong Y, Hong S. Structure-based de novo design and biochemical evaluation of novel BRAF kinase inhibitors[J]. Bioorg Med Chem Lett, 2012, 22(2):1027-1030.
[5]	Schneider G, Fechner U. Computer-based de novo design of drug-like molecules[J]. Nat Rev Drug Discov 2005, 4 (8):694-663.
[6]	Lipinski,C, Hopkins A. Navigating chemical space for biology and medicine[J]. Nature, 2004,432(7019):855-861.
[7]	Platania CB, Salomone S, Leggio GM, et al. Homology modeling of dopamine d(2) and d(3) receptors:molecular dynamics refinement and docking evaluation[J]. PloS One, 2012, 7 (9):44316.
[8]	Keseru GM, Makara GM. Hit discovery and hit-to-lead approaches[J]. Drug Discov Today, 2006, 11(15-16), 741-748.
[9]	Bohm HJ. The computer program LUDI:a new method for de novo design of enzyme inhibitors[J]. J Comput Aided Mol Des, 1992, 6 (1):61-78.
[10]	Wang RX, Gao Y, Lai LH. LigBuilder:a multi-purpose progrom for structure-based drug design[J]. J Mol Model, 2000, 6 (7-8); 498-516.
[11]	Wang RX, Liu L, Lai LH, et al. SCORE:A new empirical method for estimating the binding affinity of a protein-ligand complex[J]. J Mol Model, 1998, 4 (12):370-394.
[12]	Yuan,YX, Pei JF, Lai LH. LigBuilder 2:a practical de novo drug design approach[J]. J Chem Inform Model, 2011, 51 (5):1083-1091.
[13]	Cramer RD. Design and preliminary results of LeapFrog, a second generation de novo drug discovery tool[J]. J Mol Graphics, 1993, 11(4); 271-272.
[14]	Ambure PS, Gangwal RP, Sanganwar AT. 3D-QSAR and molecular docking analysis of biphenyl amide derivatives as p38α mitogen-activated protein kinase inhibitors[J]. Mol Divers, 2012,16(2):377-388.
[15]	Makhija MT, Kasliwal RT, Kulkarni VM, et al. De novo design and synthesis of HIV-1 integrase inhibitors[J]. Bioorg Med Chem, 2004, 12(9):2317-2333.
[16]	Schinerider G, Neidhart W, Giller T, et al. Scaffold-Hopping by topological search:a contribution to virtual screening[J]. Angewandte Chemie (International Ed. in English), Angew Chem Int Ed Engl, 1999, 38(19):2894-2896.
[17]	Schneider G. De novo design-hopping against hope[EB/OL]. Drug Discovery Today:Technologies.(2012-06-20)[2013-01-02].
[18]	Wolber G. 3D pharmacophore elucidation and virtual screening[J]. Drug Discov Today, 2010, 7(4):203-204.
[19]	Lauri G, Bartlett PA. CAVEAT:a program to facilitate the design of organic molecules[J]. J Comput Aided Mol Des, 1994, 8(1):51-66.
[20]	Beno BR, Langley DR. MORPH:a new tool for ligand design[J]. J Chem Inform Model, 2010, 50(6):1159-1164.
[21]	Maass P, Schulz-Gasch T, Stahl M, et al. Recore:a fast and versatile method for scaffold hopping based on small molecule crystal structure conformations[J]. J Chem Inform Model, 2007,47(2):390-399.
[22]	Gillet VJ, Newell W, Mata P, et al. SPROUT:recent developments in the de novo design of molecules[J]. J Chem Inform Comput Sci, 1994, 34:207-217.
[23]	Vinkers HM, de Jonge MR, Daeyaert FF, et al. SYNOPSIS:SYNthesize and optimize system in silico[J]. J Med Chem, 2003, 46:2765-2773.
[24]	Pierce AC, Rao G, Bemis GW, et al. BREED generating novel inhibitors through hybridization of known ligands. Aplication to CDK2, p38and HIV protease[J]. J Med Chem, 2004, 47:2768-2775.
[25]	Marra E, Palombo F, Ciliberto G, et al. Intratumoral electro-transfer of small interfering RNA against kinesin spindle protein (KSP) slows down tumor progression[J]. J Cell Physiol, 2013,228(1),58-64.
[26]	Jiang,C, Yang L, Wu WT, et al. De novo design, synthesis and biological evaluation of 1,4-dihydroquinolin-4-ones and 1,2,3,4-tetrahydroquinazolin-4-ones as potent kinesin spindle protein (KSP) inhibitors[J]. Bioorg Med Chem, 2011,19 (18):5612-5627.
[27]	Kim LA, D'Amore PA. A brief history of anti-VEGF for the treatment of ocular angiogenesis[J]. Am J Pathol, 2012, 181(2):376-379.
[28]	Uno M, Ban HS, Nabeyama W, et al. De novo design and synthesis of N-benzylanilines as new candidates for VEGFR tyrosine kinase inhibitors[J]. Org Biomol Chem, 2008, 6 (6):979-981.
[29]	Albert H, Santos S, Battaqlia E, et al. Differential expression of CDC25 phosphatases splice variants in human breast cancer cells[J]. Clin Chem Lab Med, 2011, 49(10):1707-1714.
[30]	Park H, Bahn YJ, Ryu SE, Structure-based de novo design and biochemical evaluation of novel Cdc25 phosphatase inhibitors[J]. Bioorg Med Chem Lett, 2009, 19(15):4330-4334.
[31]	Zhou DJ, Mei Q, Li JT, et al, Cyclophilin A and viral infections[J]. Bioch Biophys Res Comm, 2012,424(4), 647-650.
[32]	Choi KJ, Piao YJ, Lim MJ, et al. Overexpressed cyclophilin A in cancer cells renders resistance to hypoxia-and cisplatin-induced cell death[J]. Cancer Res, 2007, 67(8):3654-3662.
[33]	Ni SS, Yuan YX, Huang J, et al. Discovering potent small molecule inhibitors of cyclophilin A using de novo drug design approach[J]. J Med Chem, 2009, 52(17):5295-5298.
[34]	Wong C, Chen S. The development,application and limitations of breast cancer cell lines to study tamoxifen and aromataes inhibitor resistance[J]. J Steroid Biochem Mol Biol, 2012, 131(3-5):83-92.
[35]	Gueto C, Torres J, Vivas-Reyes R. CoMFA, LeapFrog and blind docking studies on sulfonanilide derivatives acting as selective aromatase expression regulators[J]. Eur J Med Chem, 2009, 44(9):3445-3451.
[36]	Su B, Diaz-Cruz ES, Landini S, et al. Novel sulfonanilide analoguew suppress aromataes expression and activity in breast cancer cells independent of COX-2 inhibiton[J]. J Med Chem, 2006, 49(4):1413-1419.
[37]	Davies H, Bignell GR, Cox C, et al. Mutations of the B-raf gene in human cancer[J]. Nature, 2002, 417(6892), 949-954.
[38]	Gopalsamy A, Shi M, Hu Y, et al. B-raf kinase inhibitors:hit enrichment through scaffold hopping[J]. Bioorg Med Chem Lett, 2010, 20(8):2431-2434.

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Applications of the common software and methods of denovo drug design in the antitumor drug design

doi: 10.3969/j.issn.1006-0111.2014.01.003

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通讯作者: 陈斌, bchen63@163.com

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Applications of the common software and methods of denovo drug design in the antitumor drug design

doi: 10.3969/j.issn.1006-0111.2014.01.003

Institute of Pharmacy and Pharmacology, University of South China, Hunan Hengyang 421001, China

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Applications of the common software and methods of denovo drug design in the antitumor drug design

doi: 10.3969/j.issn.1006-0111.2014.01.003

Abstract

References

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通讯作者: 陈斌, bchen63@163.com

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Related

Proportional views

Applications of the common software and methods of denovo drug design in the antitumor drug design

doi: 10.3969/j.issn.1006-0111.2014.01.003

Institute of Pharmacy and Pharmacology, University of South China, Hunan Hengyang 421001, China

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