Araştırma Makalesi
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ÖNEMLİ ORTAK ÖZELLİKLERİ TANIMLAMAK AMACIYLA, BİLİNEN MMP-9 ENZİM İNHİBİTÖRLERİ ÜZERİNDE YAPILAN FARMAKOFOR MODELLEME ÇALIŞMALARI

Yıl 2020, Cilt 44, Sayı 2, 204 - 210, 31.05.2020
https://doi.org/10.33483/jfpau.690373

Öz

Amaç: Bu çalışmada, yapı-aktivite ilişkilerini açıklamak amacıyla bilinen MMP-9 inhibitörleri üzerinden farmakofor modeller oluşturuldu.
Gereç ve Yöntem: Bilinen MMP-9 inhibitörlerinin ortak farmakoforik özellikleri belirlenerek, yapı-aktivite ilişkilerini açıklamak üzere farmakofor modeller oluşturuldu. Bu çalışma için Discovery Studio 3.5 programı kullanıldı. Bilinen MMP-9 inhibitörleri (NFH, Batimastat, Marimastat, Prinomastat, CGS-27023A ve Ro32-3555), ortak farmakofor özelliklerin belirlenmesinde kullanıldı. İki hidrojen bağı alıcısı, bir hidrojen bağı donörü ve bir hidrofobik özellik içeren hipotez seçildi.
Sonuç ve Tartışma: CGS-27023A ve Ro32-3555 dışındaki test edilen tüm inhibitörler, seçilen farmakofor modele mükemmel bir şekilde uydu. Bu iki inhibitör A2 özelliğine uymadı. Buna göre, etki için verilen konumlardaki A1, D1 ve H1 özelliklerinin gerekli olabileceği sonucuna varıldı. Ayrıca, önemli etkileşimleri tanımlamak için farmakofor model, NFH ve MMP-9 enzim kompleksi ile karşılaştırıldı. Tüm farmakoforik özelliklerin verilen pozisyonlarda, protein ile bir etkileşim gözlendi. Bu durum farmakofor hipotezimizi de desteklemektedir. Sonuç olarak, bu farmakofor model, MMP-9 enziminin yeni küçük molekül inhibitörlerini tasarlamak için yararlı olabilir.

Kaynakça

  • 1. Alexander, C. M. & Werb, Z. (1991). Extracellular matrix degradation. In Cell Biology of the Extracellular Matrix (Hay, E. D., ed.), pp. 255–302, Plenum Press, New York.
  • 2. Murphy, G. & Reynolds, J. (1993). Extracellular matrix degradation. In Connective Tissue and its Heritable Disorders (Royce, P. M. & Steinman, B., eds), pp. 287–316, Wiley-Liss, New York.
  • 3. Birkedal-Hansen, H. (1995). Proteolytic remodeling of extracellular matrix. Curr. Opin. Cell Biol. 7, 728–735.
  • 4. Whittaker, M., Floyd, C. D., Brown, P. & Gearing, A. J. H. (1999). Design and therapeutic application of matrix metalloproteinase inhibitors. Chem. Rev. 99, 2735–2776.
  • 5. Brown, D. L., Hibbs, M. S., Kearney, M., Loushin, C.& Isner, J. M. (1995). Identification of 92 kD gelatinase in human coronary atherosclerotic lesions. Association of active enzyme synthesis with unstable angina. Circulation, 91, 2125–2131.
  • 6. Rohde, L. E., Ducharme, A., Arroyo, L. H., Aikawa, M., Sukhova, G. H., Lopez-Anaya, A. et al. (1999). Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation, 99, 3063–3070.
  • 7. Sian Rowsell, Paul Hawtin, Claire A. Minshull, Holly Jepson Sarah M. V. Brockbank, Derek G. Barratt, Anthony M. Slater William L. McPheat, David Waterson, Adriano M. Henney and Richard A. Pauptit Crystal Structure of Human MMP9 in Complex with a Reverse Hydroxamate Inhibitor. J. Mol. Biol. (2002) 319, 173–181.
  • 8. PING-PING H. LEE, JIUAN-JIUAN HWANG, GILLIAN MURPHY, AND MARGOT M. IPFunctional Significance of MMP-9 in Tumor Necrosis Factor-Induced Proliferation and Branching Morphogenesis of Mammary Epithelial Cells. (2000) 141 (10), 3764-3773.
  • 9. Joshua M. Barnett, Gary W. McCollum, Jessica A. Fowler, James J.-W. Duan, Jesse D. Kay, Rui-Qin Liu, David P. Bingaman, and John S. Penn. Pharmacologic and Genetic Manipulation of Matrix Metalloproteinases -2 and -9 Reduce Retinal Neovascularization in Rodent Models of Retinopathy of Prematurity. Invest Ophthalmol Vis Sci. (2007), 48(2): 907–915.
  • 10. Caitlin A. Orner, B.A., Michael B. Geary, B.A., Warren C. Hammert, D.D.S, M.D., Regis J. O'Keefe, M.D., Ph.D., and Alayna E. Loiselle, Ph.D. Low-dose and short-duration Matrix Metalloproteinase 9 Inhibition does not affect adhesion formation during murine flexor tendon healing. (2016) 137(3): 545–553.
  • 11. Jeremy I. Levin, Yansong Gu, Frances C. Nelson, Arie Zask, John F. DiJoseph, Michele A. Sharr, Amy Sung, Guixian Jin, Rebecca Cowling, Pranab Chanda, Scott Cosmi, Chu-Lai Hsiao, Wade Edris, James Wilhelm, Loran M. Killar and Jerauld S. Skotnicki. Heteroaryl and Cycloalkyl Sulfonamide Hydroxamic Acid Inhibitors of Matrix Metalloproteinases. Bioorganic & Medicinal Chemistry Letters 11 (2001) 239-242.
  • 12. Manuel Hidalgo, S. Gail Eckhardt. Development of Matrix Metalloproteinase Inhibitors in Cancer Therapy. Journal of the National Cancer Institute, Vol. 93, No. 3, February 7, 2001.
  • 13. E. M. Krovat, K. H. Fruhwirth, T. Langer. Pharmacophore identification, in silico screening, and virtual library design for inhibitors of the human factor Xa. J. Chem. Inf. Model. 2005, 45, 146–159.
  • 14. A. Smellie, S. L. Teig, P. Towbin, Poling: Promoting conformational variation J. Comput. Chem. 1995, 16, 171–187.
  • 15. Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment, Release 2017, San Diego: Dassault Systèmes, 2016.

PHARMACOPHORE MODELING STUDIES ON KNOWN MMP-9 ENZYME INHIBITORS TO IDENTIFY THE IMPORTANT COMMON FEATURES

Yıl 2020, Cilt 44, Sayı 2, 204 - 210, 31.05.2020
https://doi.org/10.33483/jfpau.690373

Öz

Objective: In this study, pharmacophore models were generated to explain the structure–activity relationships by using the known MMP-9 inhibitors.
Material and Method: Pharmacophore models were generated to explain the specification of the structure–activity relationships of common pharmacophoric sites of the known MMP-9 inhibitors. For this study Discovery Studio 3.5 software was used. A set of known MMP-9 inhibitors (NFH, Batimastat, Marimastat, Prinomastat, CGS-27023A, and Ro32-3555) were used for common feature pharmacophore generation method. Selected hypothesis included two hydrogen bond acceptor, one hydrogen bond donor, and one hydrophobic feature.
Result and Discussion: All of the tested inhibitors except CGS-27023A and Ro32-3555 fitted the selected pharmacophore model perfectly. These two inhibitors did not fit the A2 feature. It can be concluded that A1, D1, and H1 features at the given positions could be necessary for the activity. Additionally, we compared the pharmacophore model with NFH and MMP-9 enzyme complex to identify the important interactions. At the given positions of all of the pharmacophoric features, there is an interaction with the protein. This is also supported our pharmacophore hypothesis. As a result, this pharmacophore model could be useful to design new small molecule inhibitors of MMP-9 enzyme.

Kaynakça

  • 1. Alexander, C. M. & Werb, Z. (1991). Extracellular matrix degradation. In Cell Biology of the Extracellular Matrix (Hay, E. D., ed.), pp. 255–302, Plenum Press, New York.
  • 2. Murphy, G. & Reynolds, J. (1993). Extracellular matrix degradation. In Connective Tissue and its Heritable Disorders (Royce, P. M. & Steinman, B., eds), pp. 287–316, Wiley-Liss, New York.
  • 3. Birkedal-Hansen, H. (1995). Proteolytic remodeling of extracellular matrix. Curr. Opin. Cell Biol. 7, 728–735.
  • 4. Whittaker, M., Floyd, C. D., Brown, P. & Gearing, A. J. H. (1999). Design and therapeutic application of matrix metalloproteinase inhibitors. Chem. Rev. 99, 2735–2776.
  • 5. Brown, D. L., Hibbs, M. S., Kearney, M., Loushin, C.& Isner, J. M. (1995). Identification of 92 kD gelatinase in human coronary atherosclerotic lesions. Association of active enzyme synthesis with unstable angina. Circulation, 91, 2125–2131.
  • 6. Rohde, L. E., Ducharme, A., Arroyo, L. H., Aikawa, M., Sukhova, G. H., Lopez-Anaya, A. et al. (1999). Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation, 99, 3063–3070.
  • 7. Sian Rowsell, Paul Hawtin, Claire A. Minshull, Holly Jepson Sarah M. V. Brockbank, Derek G. Barratt, Anthony M. Slater William L. McPheat, David Waterson, Adriano M. Henney and Richard A. Pauptit Crystal Structure of Human MMP9 in Complex with a Reverse Hydroxamate Inhibitor. J. Mol. Biol. (2002) 319, 173–181.
  • 8. PING-PING H. LEE, JIUAN-JIUAN HWANG, GILLIAN MURPHY, AND MARGOT M. IPFunctional Significance of MMP-9 in Tumor Necrosis Factor-Induced Proliferation and Branching Morphogenesis of Mammary Epithelial Cells. (2000) 141 (10), 3764-3773.
  • 9. Joshua M. Barnett, Gary W. McCollum, Jessica A. Fowler, James J.-W. Duan, Jesse D. Kay, Rui-Qin Liu, David P. Bingaman, and John S. Penn. Pharmacologic and Genetic Manipulation of Matrix Metalloproteinases -2 and -9 Reduce Retinal Neovascularization in Rodent Models of Retinopathy of Prematurity. Invest Ophthalmol Vis Sci. (2007), 48(2): 907–915.
  • 10. Caitlin A. Orner, B.A., Michael B. Geary, B.A., Warren C. Hammert, D.D.S, M.D., Regis J. O'Keefe, M.D., Ph.D., and Alayna E. Loiselle, Ph.D. Low-dose and short-duration Matrix Metalloproteinase 9 Inhibition does not affect adhesion formation during murine flexor tendon healing. (2016) 137(3): 545–553.
  • 11. Jeremy I. Levin, Yansong Gu, Frances C. Nelson, Arie Zask, John F. DiJoseph, Michele A. Sharr, Amy Sung, Guixian Jin, Rebecca Cowling, Pranab Chanda, Scott Cosmi, Chu-Lai Hsiao, Wade Edris, James Wilhelm, Loran M. Killar and Jerauld S. Skotnicki. Heteroaryl and Cycloalkyl Sulfonamide Hydroxamic Acid Inhibitors of Matrix Metalloproteinases. Bioorganic & Medicinal Chemistry Letters 11 (2001) 239-242.
  • 12. Manuel Hidalgo, S. Gail Eckhardt. Development of Matrix Metalloproteinase Inhibitors in Cancer Therapy. Journal of the National Cancer Institute, Vol. 93, No. 3, February 7, 2001.
  • 13. E. M. Krovat, K. H. Fruhwirth, T. Langer. Pharmacophore identification, in silico screening, and virtual library design for inhibitors of the human factor Xa. J. Chem. Inf. Model. 2005, 45, 146–159.
  • 14. A. Smellie, S. L. Teig, P. Towbin, Poling: Promoting conformational variation J. Comput. Chem. 1995, 16, 171–187.
  • 15. Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment, Release 2017, San Diego: Dassault Systèmes, 2016.

Ayrıntılar

Birincil Dil İngilizce
Konular Farmakoloji ve Eczacılık
Bölüm Araştırma Makalesi
Yazarlar

Tugba ERTAN-BOLELLİ
ANKARA ÜNİVERSİTESİ, ECZACILIK FAKÜLTESİ
0000-0001-9740-7023
Türkiye


Kayhan BOLELLİ (Sorumlu Yazar)
Ankara Üniversitesi Eczacılık Fakültesi
0000-0002-2179-997X
Türkiye

Yayımlanma Tarihi 31 Mayıs 2020
Yayınlandığı Sayı Yıl 2020, Cilt 44, Sayı 2

Kaynak Göster

Bibtex @araştırma makalesi { jfpanu690373, journal = {Journal of Faculty of Pharmacy of Ankara University}, issn = {1015-3918}, eissn = {2564-6524}, address = {Ankara University Faculty of Pharmacy Degol Str. TR-06100 Tandogan/Ankra/TURKEY}, publisher = {Ankara Üniversitesi}, year = {2020}, volume = {44}, pages = {204 - 210}, doi = {10.33483/jfpau.690373}, title = {PHARMACOPHORE MODELING STUDIES ON KNOWN MMP-9 ENZYME INHIBITORS TO IDENTIFY THE IMPORTANT COMMON FEATURES}, key = {cite}, author = {Ertan-bolelli, Tugba and Bolelli, Kayhan} }
APA Ertan-bolelli, T. & Bolelli, K. (2020). PHARMACOPHORE MODELING STUDIES ON KNOWN MMP-9 ENZYME INHIBITORS TO IDENTIFY THE IMPORTANT COMMON FEATURES . Journal of Faculty of Pharmacy of Ankara University , 44 (2) , 204-210 . DOI: 10.33483/jfpau.690373
MLA Ertan-bolelli, T. , Bolelli, K. "PHARMACOPHORE MODELING STUDIES ON KNOWN MMP-9 ENZYME INHIBITORS TO IDENTIFY THE IMPORTANT COMMON FEATURES" . Journal of Faculty of Pharmacy of Ankara University 44 (2020 ): 204-210 <https://dergipark.org.tr/tr/pub/jfpanu/issue/53357/690373>
Chicago Ertan-bolelli, T. , Bolelli, K. "PHARMACOPHORE MODELING STUDIES ON KNOWN MMP-9 ENZYME INHIBITORS TO IDENTIFY THE IMPORTANT COMMON FEATURES". Journal of Faculty of Pharmacy of Ankara University 44 (2020 ): 204-210
RIS TY - JOUR T1 - PHARMACOPHORE MODELING STUDIES ON KNOWN MMP-9 ENZYME INHIBITORS TO IDENTIFY THE IMPORTANT COMMON FEATURES AU - Tugba Ertan-bolelli , Kayhan Bolelli Y1 - 2020 PY - 2020 N1 - doi: 10.33483/jfpau.690373 DO - 10.33483/jfpau.690373 T2 - Journal of Faculty of Pharmacy of Ankara University JF - Journal JO - JOR SP - 204 EP - 210 VL - 44 IS - 2 SN - 1015-3918-2564-6524 M3 - doi: 10.33483/jfpau.690373 UR - https://doi.org/10.33483/jfpau.690373 Y2 - 2020 ER -
EndNote %0 Ankara Üniversitesi Eczacılık Fakültesi Dergisi PHARMACOPHORE MODELING STUDIES ON KNOWN MMP-9 ENZYME INHIBITORS TO IDENTIFY THE IMPORTANT COMMON FEATURES %A Tugba Ertan-bolelli , Kayhan Bolelli %T PHARMACOPHORE MODELING STUDIES ON KNOWN MMP-9 ENZYME INHIBITORS TO IDENTIFY THE IMPORTANT COMMON FEATURES %D 2020 %J Journal of Faculty of Pharmacy of Ankara University %P 1015-3918-2564-6524 %V 44 %N 2 %R doi: 10.33483/jfpau.690373 %U 10.33483/jfpau.690373
ISNAD Ertan-bolelli, Tugba , Bolelli, Kayhan . "PHARMACOPHORE MODELING STUDIES ON KNOWN MMP-9 ENZYME INHIBITORS TO IDENTIFY THE IMPORTANT COMMON FEATURES". Journal of Faculty of Pharmacy of Ankara University 44 / 2 (Mayıs 2020): 204-210 . https://doi.org/10.33483/jfpau.690373
AMA Ertan-bolelli T. , Bolelli K. PHARMACOPHORE MODELING STUDIES ON KNOWN MMP-9 ENZYME INHIBITORS TO IDENTIFY THE IMPORTANT COMMON FEATURES. Ankara Ecz. Fak. Derg.. 2020; 44(2): 204-210.
Vancouver Ertan-bolelli T. , Bolelli K. PHARMACOPHORE MODELING STUDIES ON KNOWN MMP-9 ENZYME INHIBITORS TO IDENTIFY THE IMPORTANT COMMON FEATURES. Journal of Faculty of Pharmacy of Ankara University. 2020; 44(2): 204-210.
IEEE T. Ertan-bolelli ve K. Bolelli , "PHARMACOPHORE MODELING STUDIES ON KNOWN MMP-9 ENZYME INHIBITORS TO IDENTIFY THE IMPORTANT COMMON FEATURES", Journal of Faculty of Pharmacy of Ankara University, c. 44, sayı. 2, ss. 204-210, May. 2020, doi:10.33483/jfpau.690373

Kapsam ve Amaç

Ankara Üniversitesi Eczacılık Fakültesi Dergisi, açık erişim, hakemli bir dergi olup Türkçe veya İngilizce olarak farmasötik bilimler alanındaki önemli gelişmeleri içeren orijinal araştırmalar, derlemeler ve kısa bildiriler için uluslararası bir yayım ortamıdır. Bilimsel toplantılarda sunulan bildiriler supleman özel sayısı olarak dergide yayımlanabilir. Ayrıca, tüm farmasötik alandaki gelecek ve önceki ulusal ve uluslararası bilimsel toplantılar ile sosyal aktiviteleri içerir.