Comparative study between 3D-QSAR and Docking-Based Pharmacophore models for potent Plasomodium falciparum dihydroorotate dehydrogenase inhibitors

Tien-Sheng Tseng, Yu-Ching Lee, Nai-Wan Hsiao, Yun-Ru Liu, Keng-Chang Tsai

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Malaria, caused by infections of the human malaria parasites Plasmodium falciparum, is a global infectious parasitic disease. Each year, about three million people died from malaria and the majority of whom are pregnant women and young children. Recently, a number of research attempt to reduce malaria parasite resistance and the toxicity of anti-malarial drugs. Nowadays, Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a potent drug target to inhibit malarial activity by blocking pyrimidine biosynthesis. In this study, we employed 3D-QSAR Pharmacophore Generation and Docking-Based Pharmacophore Development to build the pharmacophore by using the collected 67 effective inhibitors against PfDHODH. 3D-QSAR Pharmacophore model, Hypo1, shows the high correlation coefficient (0.935), the lowest RMS deviation (2.15), the predicting accuracy of successful rates to training set (89.4%) and test set compounds (72.4%), respectively, revealing favorable predictive ability and is a reliable for further study. Additionally, Docking-Based Pharmacophore model, DBP-All255, exhibits comparable predictive capability to that of Hypo1, while DBP-Top1 shows poor statistical significance. This study reveals pharmacophore features of Hypo1, built by 3D-QSAR Pharmacophore Generation, are well-complementary to the functional residues in the active site of PfDHODH and is of great reliable for database screening. © 2015 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)265-271
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number2
DOIs
Publication statusPublished - 2016

Fingerprint

Quantitative Structure-Activity Relationship
Plasmodium falciparum
Malaria
Parasites
Parasitic Diseases
Falciparum Malaria
Biosynthesis
Antimalarials
Pharmaceutical Preparations
Communicable Diseases
Toxicity
Pregnant Women
Catalytic Domain
Screening
Databases
Infection
Research
dihydroorotate dehydrogenase

Keywords

  • 3D-QSAR Pharmacophore Generation
  • Catalyst
  • Docking-Based Pharmacophore Development
  • PfDHODH inhibitor
  • Pharmacophore
  • dihydroorotate dehydrogenase
  • dihydroorotate dehydrogenase inhibitor
  • accuracy
  • antimalarial activity
  • Article
  • correlation coefficient
  • drug potency
  • drug targeting
  • IC50
  • intermethod comparison
  • malaria
  • molecular docking
  • nonhuman
  • pharmacophore
  • Plasmodium falciparum
  • quantitative structure activity relation

Cite this

Comparative study between 3D-QSAR and Docking-Based Pharmacophore models for potent Plasomodium falciparum dihydroorotate dehydrogenase inhibitors. / Tseng, Tien-Sheng; Lee, Yu-Ching; Hsiao, Nai-Wan; Liu, Yun-Ru; Tsai, Keng-Chang.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 2, 2016, p. 265-271.

Research output: Contribution to journalArticle

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title = "Comparative study between 3D-QSAR and Docking-Based Pharmacophore models for potent Plasomodium falciparum dihydroorotate dehydrogenase inhibitors",
abstract = "Malaria, caused by infections of the human malaria parasites Plasmodium falciparum, is a global infectious parasitic disease. Each year, about three million people died from malaria and the majority of whom are pregnant women and young children. Recently, a number of research attempt to reduce malaria parasite resistance and the toxicity of anti-malarial drugs. Nowadays, Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a potent drug target to inhibit malarial activity by blocking pyrimidine biosynthesis. In this study, we employed 3D-QSAR Pharmacophore Generation and Docking-Based Pharmacophore Development to build the pharmacophore by using the collected 67 effective inhibitors against PfDHODH. 3D-QSAR Pharmacophore model, Hypo1, shows the high correlation coefficient (0.935), the lowest RMS deviation (2.15), the predicting accuracy of successful rates to training set (89.4{\%}) and test set compounds (72.4{\%}), respectively, revealing favorable predictive ability and is a reliable for further study. Additionally, Docking-Based Pharmacophore model, DBP-All255, exhibits comparable predictive capability to that of Hypo1, while DBP-Top1 shows poor statistical significance. This study reveals pharmacophore features of Hypo1, built by 3D-QSAR Pharmacophore Generation, are well-complementary to the functional residues in the active site of PfDHODH and is of great reliable for database screening. {\circledC} 2015 Elsevier Ltd. All rights reserved.",
keywords = "3D-QSAR Pharmacophore Generation, Catalyst, Docking-Based Pharmacophore Development, PfDHODH inhibitor, Pharmacophore, dihydroorotate dehydrogenase, dihydroorotate dehydrogenase inhibitor, accuracy, antimalarial activity, Article, correlation coefficient, drug potency, drug targeting, IC50, intermethod comparison, malaria, molecular docking, nonhuman, pharmacophore, Plasmodium falciparum, quantitative structure activity relation",
author = "Tien-Sheng Tseng and Yu-Ching Lee and Nai-Wan Hsiao and Yun-Ru Liu and Keng-Chang Tsai",
note = "Export Date: 28 March 2016 CODEN: BMCLE 通訊地址: Tsai, K.-C.; National Research Institute of Chinese Medicine, No. 155-1, Sec. 2, Linong St., Taiwan; 電子郵件: tkc@nricm.edu.tw 化學物質/CAS: dihydroorotate dehydrogenase, 9029-03-2 出資詳情: 103-2320-B-077-001-MY3, MOST, Ministry of Science and Technology 出資詳情: MOHW104-TDU-B-212-124-001, MOHW, Ministry of Science and Technology 參考文獻: Fidock, D.A., Rosenthal, P.J., Croft, S.L., Brun, R., Nwaka, S., (2004) Nat. Rev. Drug Disc., 3, p. 509; Cui, L., Su, X.Z., (2009) Expert Rev. Anti-Infect. Ther., 7, p. 999; Pohlit, A.M., Lima, R.B., Frausin, G., Silva, L.F., Lopes, S.C., Moraes, C.B., Cravo, P., Costa, F.T., (2013) Molecules, 18, p. 9219; Schwartz, L., Brown, G.V., Genton, B., Moorthy, V.S., (2012) Malar. J., 11, p. 11; Challenges in Malaria Research: Core Science and Innovation (2014) Malar. J., 13, pp. O2-P107; Downie, M.J., Kirk, K., Mamoun, C.B., (2008) Eukaryot. Cell, 7, p. 1231; Baldwin, J., Farajallah, A.M., Malmquist, N.A., Rathod, P.K., Phillips, M.A., (2002) J. Biol. Chem., 277, p. 41827; Phillips, M.A., Rathod, P.K., (2010) Infect. Disord. Drug Targets, 10, p. 226; (2005) Catalyst. Version 4.11 (Software Package), , http://www.accelrys.com, Accelry: San Diego, CA; Debnath, A.K., (2002) J. Med. Chem., 45, p. 41; Du, L.P., Tsai, K.C., Li, M.Y., You, Q.D., Xia, L., (2004) Bioorg. Med. Chem. Lett., 14, p. 4771; Li, M.Y., Tsai, K.C., Xia, L., (2005) Bioorg. Med. Chem. Lett., 15, p. 657; Gujjar, R., Marwaha, A., El Mazouni, F., White, J., White, K.L., Creason, S., Shackleford, D.M., Phillips, M.A., (2009) J. Med. Chem., 52, p. 1864; Phillips, M.A., Gujjar, R., Malmquist, N.A., White, J., El Mazouni, F., Baldwin, J., Rathod, P.K., (2008) J. Med. Chem., 51, p. 3649; Davies, M., Heikkila, T., McConkey, G.A., Fishwick, C.W., Parsons, M.R., Johnson, A.P., (2009) J. Med. Chem., 52, p. 2683; Boa, A.N., Canavan, S.P., Hirst, P.R., Ramsey, C., Stead, A.M., McConkey, G.A., (2005) Bioorg. Med. Chem., 13, p. 1945; Heikkila, T., Thirumalairajan, S., Davies, M., Parsons, M.R., McConkey, A.G., Fishwick, C.W., Johnson, A.P., (2006) Bioorg. Med. Chem. Lett., 16, p. 88; Brooks, B.R., Brooks, C.L., 3rd, Mackerell, A.D., Jr., Nilsson, L., Petrella, R.J., Roux, B., Won, Y., Karplus, M., (2009) J. Comput. Chem., 30, p. 1545; Smellie, S.L.T.A., Tobwin, P., (1995) J. Comput. Chem., 16, p. 171; Sprague, P.W., (1995) Perspect. Drug Discovery Des., 3, p. 1",
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TY - JOUR

T1 - Comparative study between 3D-QSAR and Docking-Based Pharmacophore models for potent Plasomodium falciparum dihydroorotate dehydrogenase inhibitors

AU - Tseng, Tien-Sheng

AU - Lee, Yu-Ching

AU - Hsiao, Nai-Wan

AU - Liu, Yun-Ru

AU - Tsai, Keng-Chang

N1 - Export Date: 28 March 2016 CODEN: BMCLE 通訊地址: Tsai, K.-C.; National Research Institute of Chinese Medicine, No. 155-1, Sec. 2, Linong St., Taiwan; 電子郵件: tkc@nricm.edu.tw 化學物質/CAS: dihydroorotate dehydrogenase, 9029-03-2 出資詳情: 103-2320-B-077-001-MY3, MOST, Ministry of Science and Technology 出資詳情: MOHW104-TDU-B-212-124-001, MOHW, Ministry of Science and Technology 參考文獻: Fidock, D.A., Rosenthal, P.J., Croft, S.L., Brun, R., Nwaka, S., (2004) Nat. Rev. Drug Disc., 3, p. 509; Cui, L., Su, X.Z., (2009) Expert Rev. Anti-Infect. Ther., 7, p. 999; Pohlit, A.M., Lima, R.B., Frausin, G., Silva, L.F., Lopes, S.C., Moraes, C.B., Cravo, P., Costa, F.T., (2013) Molecules, 18, p. 9219; Schwartz, L., Brown, G.V., Genton, B., Moorthy, V.S., (2012) Malar. J., 11, p. 11; Challenges in Malaria Research: Core Science and Innovation (2014) Malar. J., 13, pp. O2-P107; Downie, M.J., Kirk, K., Mamoun, C.B., (2008) Eukaryot. Cell, 7, p. 1231; Baldwin, J., Farajallah, A.M., Malmquist, N.A., Rathod, P.K., Phillips, M.A., (2002) J. Biol. Chem., 277, p. 41827; Phillips, M.A., Rathod, P.K., (2010) Infect. Disord. Drug Targets, 10, p. 226; (2005) Catalyst. Version 4.11 (Software Package), , http://www.accelrys.com, Accelry: San Diego, CA; Debnath, A.K., (2002) J. Med. Chem., 45, p. 41; Du, L.P., Tsai, K.C., Li, M.Y., You, Q.D., Xia, L., (2004) Bioorg. Med. Chem. Lett., 14, p. 4771; Li, M.Y., Tsai, K.C., Xia, L., (2005) Bioorg. Med. Chem. Lett., 15, p. 657; Gujjar, R., Marwaha, A., El Mazouni, F., White, J., White, K.L., Creason, S., Shackleford, D.M., Phillips, M.A., (2009) J. Med. Chem., 52, p. 1864; Phillips, M.A., Gujjar, R., Malmquist, N.A., White, J., El Mazouni, F., Baldwin, J., Rathod, P.K., (2008) J. Med. Chem., 51, p. 3649; Davies, M., Heikkila, T., McConkey, G.A., Fishwick, C.W., Parsons, M.R., Johnson, A.P., (2009) J. Med. Chem., 52, p. 2683; Boa, A.N., Canavan, S.P., Hirst, P.R., Ramsey, C., Stead, A.M., McConkey, G.A., (2005) Bioorg. Med. Chem., 13, p. 1945; Heikkila, T., Thirumalairajan, S., Davies, M., Parsons, M.R., McConkey, A.G., Fishwick, C.W., Johnson, A.P., (2006) Bioorg. Med. Chem. Lett., 16, p. 88; Brooks, B.R., Brooks, C.L., 3rd, Mackerell, A.D., Jr., Nilsson, L., Petrella, R.J., Roux, B., Won, Y., Karplus, M., (2009) J. Comput. Chem., 30, p. 1545; Smellie, S.L.T.A., Tobwin, P., (1995) J. Comput. Chem., 16, p. 171; Sprague, P.W., (1995) Perspect. Drug Discovery Des., 3, p. 1

PY - 2016

Y1 - 2016

N2 - Malaria, caused by infections of the human malaria parasites Plasmodium falciparum, is a global infectious parasitic disease. Each year, about three million people died from malaria and the majority of whom are pregnant women and young children. Recently, a number of research attempt to reduce malaria parasite resistance and the toxicity of anti-malarial drugs. Nowadays, Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a potent drug target to inhibit malarial activity by blocking pyrimidine biosynthesis. In this study, we employed 3D-QSAR Pharmacophore Generation and Docking-Based Pharmacophore Development to build the pharmacophore by using the collected 67 effective inhibitors against PfDHODH. 3D-QSAR Pharmacophore model, Hypo1, shows the high correlation coefficient (0.935), the lowest RMS deviation (2.15), the predicting accuracy of successful rates to training set (89.4%) and test set compounds (72.4%), respectively, revealing favorable predictive ability and is a reliable for further study. Additionally, Docking-Based Pharmacophore model, DBP-All255, exhibits comparable predictive capability to that of Hypo1, while DBP-Top1 shows poor statistical significance. This study reveals pharmacophore features of Hypo1, built by 3D-QSAR Pharmacophore Generation, are well-complementary to the functional residues in the active site of PfDHODH and is of great reliable for database screening. © 2015 Elsevier Ltd. All rights reserved.

AB - Malaria, caused by infections of the human malaria parasites Plasmodium falciparum, is a global infectious parasitic disease. Each year, about three million people died from malaria and the majority of whom are pregnant women and young children. Recently, a number of research attempt to reduce malaria parasite resistance and the toxicity of anti-malarial drugs. Nowadays, Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a potent drug target to inhibit malarial activity by blocking pyrimidine biosynthesis. In this study, we employed 3D-QSAR Pharmacophore Generation and Docking-Based Pharmacophore Development to build the pharmacophore by using the collected 67 effective inhibitors against PfDHODH. 3D-QSAR Pharmacophore model, Hypo1, shows the high correlation coefficient (0.935), the lowest RMS deviation (2.15), the predicting accuracy of successful rates to training set (89.4%) and test set compounds (72.4%), respectively, revealing favorable predictive ability and is a reliable for further study. Additionally, Docking-Based Pharmacophore model, DBP-All255, exhibits comparable predictive capability to that of Hypo1, while DBP-Top1 shows poor statistical significance. This study reveals pharmacophore features of Hypo1, built by 3D-QSAR Pharmacophore Generation, are well-complementary to the functional residues in the active site of PfDHODH and is of great reliable for database screening. © 2015 Elsevier Ltd. All rights reserved.

KW - 3D-QSAR Pharmacophore Generation

KW - Catalyst

KW - Docking-Based Pharmacophore Development

KW - PfDHODH inhibitor

KW - Pharmacophore

KW - dihydroorotate dehydrogenase

KW - dihydroorotate dehydrogenase inhibitor

KW - accuracy

KW - antimalarial activity

KW - Article

KW - correlation coefficient

KW - drug potency

KW - drug targeting

KW - IC50

KW - intermethod comparison

KW - malaria

KW - molecular docking

KW - nonhuman

KW - pharmacophore

KW - Plasmodium falciparum

KW - quantitative structure activity relation

U2 - 10.1016/j.bmcl.2015.12.043

DO - 10.1016/j.bmcl.2015.12.043

M3 - Article

VL - 26

SP - 265

EP - 271

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 2

ER -