i

SKRIPSI

ASMAUL CHUSNAH

PREDIKSI AKTIVITAS SENYAWA METABOLIT

SEKUNDER RIMPANG Homalomena occulta

SEBAGAI XANTHINE OXIDASE INHIBITOR

SECARA IN SILICO

PROGRAM STUDI FARMASI

FAKULTAS ILMU KESEHATAN

UNIVERSITAS MUHAMMADIYAH MALANG

2019

ii

iii

iv

iv

KATA PENGANTAR

Puji syukur Alhamdulilah penulis panjatkan kehadirat Allah SWT atas segala

limpahan rahmat, hidayah serta karunia-Nya, sehingga penulis dapat menyelesaikan

skripsi yang berjudul “Prediksi Aktivitas Senyawa Metabolit Sekunder Rimpang

Homalomena occulta Sebagai Xanthine Oxidase Inhibitor secara Insilico”, diajukan

untuk memenuhi persyaratan Pendidikan Sarjana Farmasi Fakultas Ilmu Kesehatan

Universitas Muhammadiyah Malang.

Pada kesempatan ini, penulis ingin menyampaikan terimakasih kepada :

1. Faqih Ruhyanudin, M. Kep., Sp. Kep. MB, selaku Dekan Fakultas Ilmu

Kesehatan Universitas Muhammadiyah Malang atas ilmu dan bimbingannya

selama di Fakultas Ilmu Kesehatan UMM.

2. Hj. Dian Ermawati, S.Farm., Apt., M.Farm., selaku Ketua Program Studi

Farmasi Universitas Muhammadiyah Malang atas ilmu dan bimbingannya

selama di Fakultas Ilmu Kesehatan UMM.

3. Sovia Aprina Basuki, S. Farm., M. Si., Apt., selaku dosen pembimbing 1 dan

M. Artabah Muchlicsin, M.Farm. selaku dosen pembimbing 2, yang telah

memberikan bimbingan dalam penyusunan skripsi dengan penuh kesabaran

dan kebaikan hati sehingga penulis dapat menyelesaikan penelitian ini dengan

baik.

4. Drs. H. Achmad Inoni, Apt., selaku dosen penguji 1 dan Engrid Juni Astuti,

M.Farm., Apt., selaku dosen penguji 2, yang telah memberikan masukan

dalam perbaikan skripsi ini serta ilmu yang sangat berharga.

5. Kedua orang tua saya Bapak Mujib dan Ibu Sahla, adik-adik saya M.

Muhaimin, M. Hanafi Afifudin dan Nailatul Mawaddah yang dengan penuh

kasih sayang selalu mendukung secara moril dan materil, mendoakan,

memberikan restu, memberi nasehat dan sebagai sumber motivasi sehingga

penulis dapat menyelesaikan naskah ini.

6. Kepada Guru saya pengasuh Pondok Pesantren Al- Muqorrobin Lawang, KH.

Ibrahim Ammari yang selalu menjadi panutan dan membimbing menjadi

muslimah yang taat kepada Allah.

v

7. Kepada seluruh Keluarga Besar Bani Manirun, Bibi di Pasuruan, Ibu Suarni,

Muslikha, Isrowiyah. Keluarga Besar Hamdani di Madura Bibi Syamsiyah,

Maimunah, Jamilah yang selalu memberikan kepercayaan.

8. Seluruh Dosen dan Staf pengajar Farmasi UMM yang telah mendidik dan

mengajarkan ilmu pengetahuan selama penulis menempuh pendidikan sarjana

Farmasi di Universitas Muhammadiyah Malang.

9. Seluruh tim skripsi in silico, Dyah Ervy Putri L., Annisa Febrianti, Farinadya

Insyafiatul M., Tika Indraningrum, Devi Kurniasih, M. Aditya Nugraha, Susi

Ernawati, dan Hendri Bagus Saputra atas kerjasama, dukungan, kesabaran, dan

kebersamaan dalam setiap suka dan duka selama mengerjakan skripsi.

10. Para sahabat Yogye Eka P, Nofitasari, Alviatun Hidayah, Revi Eltha, dan

Pipin Purwa, Aulia Olivianti telah memberi semangat, dukungan, kasih sayang

sehingga penulis bisa menyelesaikan naskah ini.

11. Kepada Khoiru Rozi, atas pengertian, kesabaran, dan selalu ada dikala penulis

membutuhkan motivasi dan telah menjadi penyemangat untuk mendapatkan

gelar sarjanah.

12. Sejawat Farmasianida 2015, keluarga besar Farmasi D dan keluarga besar

Farmasi E, yang namanya tidak dapat disebutkan satu per satu, terimakasih

atas dukungan, bantuan, dan kerjasamanya selama kuliah di Farmasi UMM.

13. Serta semua pihak dari dalam maupun luar yang telah membantu sehingga

terselesaikannya skripsi ini, terimakasih atas bantuannya dan motivasi yang

diberikan.

Penulis menyadari bahwa masih banyak kekurangan yang terdapat pada skripsi ini,

oleh karena itu penulis mengharapkan kritik dan saran yang bersifat membangun

dari berbagi pihak untuk kesempurnaan skripsi ini dan semoga dapat bermanfaat

bagi pembaca.

Malang, 15 Juni 2019

Asmaul Chusnah

x

DAFTAR ISI

Halaman

Lembar Pengesahan ......................................................................................... ii

Lembar Pengujian ............................................................................................ iii

KATA PENGANTAR ..................................................................................... iv

ABSTRAK ....................................................................................................... viii

ABSTRACT ..................................................................................................... ix

DAFTAR ISI .................................................................................................... x

DAFTAR GAMBAR ....................................................................................... xiii

DAFTAR TABEL ............................................................................................ xiv

DAFTAR LAMPIRAN .................................................................................... xv

BAB I PENDAHULUAN ............................................................................ 1

1.1 Latar Belakang ................................................................................. 1

1.2 Rumusan Masalah ............................................................................ 3

1.3 Tujuan Penelitian ............................................................................. 3

1.4 Manfaat Penelitian ........................................................................... 3

BAB II TINJAUAN PUASTAKA .................................................................. 4

2.1 Farmakodinamik ............................................................................... 4

2.1.1 Asam Amino ..................................................................................... 4

2.1.2 Reseptor ............................................................................................ 6

2.1.3 Ligan ................................................................................................. 6

2.1.4 Interaksi Ligan dengan Reseptor ....................................................... 7

2.1.5 Hubungan Struktur dan Interaksi Obat dengan Reseptor .................. 8

2.1.6 Jenis Ikatan Obat dengan Reseptor ................................................... 9

2.2 Farmakokinetik ................................................................................. 13

2.2.1 Absorbsi ............................................................................................ 14

2.2.2 Distribusi ........................................................................................... 14

2.2.3 Metabolisme ...................................................................................... 15

2.2.4 Ekskresi ............................................................................................. 15

2.2.5 Druglikeness ...................................................................................... 15

2.3 Tanaman Nampu ............................................................................... 17

2.3.1 Klasifikasi Nampu ............................................................................ 17

xi

2.3.2 Nama Daerah Nampu ....................................................................... 17

2.3.3 Morfologi dan Penyebaran ............................................................... 17

2.3.4 Manfaat Rimpang Nampu ................................................................ 18

2.3.5 Senyawa Metabolit Sekunder Rimpang Nampu .............................. 18

2.4 Hiperurisemia ................................................................................... 19

2.5 Xanthine oxidase .............................................................................. 20

2.5.1 Definisi ............................................................................................. 20

2.5.2 Mekanisme Kerja ............................................................................. 21

2.5.3 Xanthine Oxidase Inhibitor .............................................................. 22

2.6 Uji Aktivitas Secara In Silico ........................................................... 22

2.6.1 Definisi Metode In Silico ................................................................. 22

2.6.2 Jenis Metode Uji Aktivitas Secara In Silico ..................................... 23

2.6.3 Perangkat Lunak dan Database pendukung Uji In Silico ................. 23

BAB III KERANGKA KONSEPTUAL ........................................................ 28

BAB IV METODE PENELITIAN ................................................................ 30

4.1 Jenis Penelitian ................................................................................. 30

4.2 Tempat dan Waktu Penelitian .......................................................... 30

4.3 Kriteria Inklusi dan Eksklusi Penelitian ........................................... 30

4.3.1 Kriteria Inklusi ................................................................................. 30

4.3.2 Kriteria Eksklusi .............................................................................. 30

4.4 Alat dan Bahan Penelitian ................................................................ 31

4.4.1 Alat Penelitian .................................................................................. 31

4.4.2 Bahan Penelitian............................................................................... 31

4.5 Kerangka Operasional ...................................................................... 32

4.6 Prosedur Penelitian .......................................................................... 33

4.6.1 Preparasi Senyawa ........................................................................... 33

4.6.2 Pemisahan Ligan dengan Reseptor .................................................. 33

4.6.3 Preparasi Ligan dengan Reseptor ..................................................... 34

4.6.4 Validasi Metode Docking ................................................................. 34

4.6.5 Docking Senyawa Uji ....................................................................... 35

4.6.6 Validasi Metode Docking ................................................................. 34

4.6.7 Docking Ligan Senyawa Pembanding dan Senyawa Uji ................. 36

4.6.8 Pengujian Senyawa dengan SwissADME ......................................... 37

xii

4.6.9 Preparasi Senyawa Decoy ................................................................ 37

4.7 Analisis Pengolahan Data ................................................................ 38

4.7.1 Membuat Kurva ROC pada SPSS .................................................... 38

4.7.2 Visualisasi Hasil Docking ................................................................ 38

4.7.3 Rancangan Hasil Docking ................................................................ 39

BAB V HASIL PENELITIAN....................................................................... 40

5.1 Validasi Metode ............................................................................... 40

5.2 Hasil Docking Ligand dan Reseptor ................................................ 41

5.3 Visualisasi Hasil Docking Kontrol Positif ....................................... 44

5.4 Visualisasi Hasil Docking Senyawa................................................. 44

5.5 Hasil Docking Senyawa Decoy ........................................................ 54

5.6 Kurva ROC ...................................................................................... 55

5.7 Hasil Uji Farmakokinetik ................................................................. 56

BAB VI PEMBAHASAN ............................................................................... 58

BAB VII KESIMPULAN ................................................................................ 65

7.1 Kesimpulan ...................................................................................... 65

7.2 Saran .................................................................................................. 65

DAFTAR PUSTAKA ...................................................................................... 66

xiii

DAFTAR GAMBAR

Gambar Halaman

2.1 Tanaman Nampu ........................................................................................ 17

2.2 Mekanisme Kerja Xanthine Oxidase .......................................................... 20

2.3 Metabolisme Purin Menjadi Asam Urat .................................................... 21

2.4 Struktur Kimia Allopurinol ........................................................................ 22

3.1 Kerangka Konseptual Penelitian ................................................................ 26

4.1 Kerangka Operasional Penelitian ............................................................... 30

5.1 Visualisasi Ligan-Reseptor ........................................................................ 44

5.2 Kurva ROC ................................................................................................ 55

5.3 Hasil Uji Boilied-egg.................................................................................. 57

xiv

DAFTAR TABEL

Tabel Halaman

2.1 Asam Amino Berdasarkan Sifat Kelarutan ................................................ 4

2.2 Pengelompokan Asam Amino ................................................................... 5

3.3 Tipe Ikatan Kimia Beserta Contoh dan Kekuatannya ................................ 12

5.1 Validasi Metode ......................................................................................... 40

5.2 Uji Xanthine Oxidase Inhibitor dengan Reseptor 3BDJ ............................ 41

5.3 Visualisasi Hasil Docking Senyawa ........................................................... 44

5.4 Hasil Uji Senyawa Decoy .......................................................................... 54

5.5 Hasil Uji Farmakokinetik ........................................................................... 56

xv

DAFTAR LAMPIRAN

Lampiran Halaman

1. Daftar Riwayat Hidup .................................................................................. 73

2. Jadwal Kegiatan Penelitian .......................................................................... 74

3. Daftar Senyawa Metabolit Rimpang Homalomena occulta......................... 75

4 Clustering Histogram Hasil Docking Senyawa ............................................ 93

5. Visualisasi 2D dan 3D Hasil Docking .......................................................... 98

6. Daftar SMILES Senyawa Rimpang Homalomena occulta .......................... 121

7. Daftar SMILES Senyawa Decoy ................................................................. 125

8. Hasil Uji Farmakokinetika ........................................................................... 128

66

DAFTAR PUSTAKA

Accelrys. 2017. Discovery Studio : Visualization in Discovery Studio.

Accelerys Corporate Headquarters. http/www.3dsbbiovia.com, diakses

tanggal 9 Desember 2018

Anonim. 2013. Farmakologi dan Terapi UI. Jakarta: Universitas Indonesia Press

Anonim, 2013. Homalomena occulta (Lour.) Schott. The Plant

List.(http:/www.theplantlist.org/tp1.1/record/knew-100023, Diakses

tanggal 20 November 2018 )

Ardan, T., Janetta K., & Jitka C. 2003. Comparative Histochemical and

Immunohistochemical Study on Xanthine Oxidoreductase/Xantine

Oxidase in Mammalian Corneal Epithelium. Acta histochemica, 106

(2004) 69–75

Bitik, Berivan, & M. Akif Ozturk. 2014. An Old Disease with New Insights :

Update on Diagnosis and Treatment of Gout. Europian Journal of

Rheumatology, DOI: 10.5152/eurjrheumatol.2014.021

Bensky, D., Gamble, A, 1993. Chinnese Herbal Medicine: Materia medica

resived ed. Estland Press, Seatle, Washington, pp. 166.

Cos, P., Li Ying, Calomme , M., Hu, J., Cimanga, K., Van Poel, B. 1998.

Structure Activity Relationship and Classification of Flavonoids as

Inhibitors of Xanthine Oxidase and Superoxide Scavengers. Jou. Nat.

Prod 61: 71-76

Csizmadia, Peter. 1999. MarvinSketch and MarvinView : Molecule Applets for

the World Wide Web. ChemAxon Ltd., Valyog. 7, Budapest, H-1032

Dalimartha, S. 2008. Resep Obat Untuk Asam Urat. Bogor : Penebar Swadaya

Daina, A., Michielin, O., & Vincent, Z. 2017. SwissADME: a free web tool to

evaluate pharmacokinetics, drug-likeness and medical chemistry

friendliness of small molecules. Scientific Reports, 7:42717, DOI:

10.1038/srep42717

Egan, W. J., Merz, K. M. & Baldwin, J. J. 2000. Prediction of Drug Absorption

Using Multivariate Statistics. J. Med. Chem. 43, 3867–3877. DOI:

10.1021/jm000292e

67

Ekins S, Mestres J, Testa B (2007). In silico pharmacology for drug discovery:

applications to targets and beyond. Br J Pharmacol, [E-pub ahead of

print: 4 June 2007; doi:10.1038/sj.bjp.0707306].

Fatallah, S., Sahar. 2018. Uric Acid. http://www.medscape.com. Diakses tanggal

14 Oktober 2018

Fauzi, A., Putra, M.M.A. 2016. Nefrolitiasis. Majority, Vol. 5. No.2, April

2016.pp.73

Fowler, S., Roush, R., 2013 . Concept of Biology. Houston, Texas. Rice

University. p 46.

Graves, A.P, Ruth, B., Brian, K.S. 2004. Decoys for Docking. J. Med. Chem,

2005, 48, 3714-3728

Ghose, A. K., Viswanadhan, V. N. & Wendoloski, J. J. 1999. A knowledge-based

approach in designing combinatorial or medicinal chemistry libraries

for drug discovery. 1. A qualitative and quantitative characterization of

known drug databases. J Comb. Chem. 1, 55–68. 10.1021/cc9800071

Hajian, Karimollah. 2013. Receiver Operating Characteristic (ROC) Curve

Analysis for Medical Diagnostic Test Evaluation. Caspian J Intern

Med 2013; 4(2): 627-635

Han, Haewook, dkk. 2015. National Management of Kidney Stone. Clin Nutr

Res 2015;4:137-152

Hardjono, suko. 2013. Sintesis dan Uji Aktivitas Antikanker Senyawa 1-(2 -

Klorobenzoiloksi)Urea dan 1-(4-Klorobenzoiloksi)Urea. Berkala

Ilmiah Kimia Farmasi, Vol.2 No.

Harti, S.A., 2014. Biokimia Kesehatan. Yogyakarta. Nuha Medika. pp 123-128.

Harwood L.M., McKendrick J.E., Whitehead R.C., 2008. At a Glance Kimia

Organik. Erlangga. Jakarta

Hevener, K. E., Zhao, W., Ball, D. M., Babaoglu, K., Qi, J., White, S. W., & Lee,

R. E. 2009. Validation of Molecular Docking Programs for Virtual

Screening against Dihydropteroate Synthase. Journal of Chemical

Information and Modeling, 49(2), 444–460.doi:10.1021/ci800293n

68

Hille, Russ, James Hall, dan Partha Basu. 2014. The Mononuclear Molybdenum

Enzymes. Chem. Rev. 2014, 114, 3963−4038

Hunter, C.A., & Sanders, J.K. M., 1990. The nature of .pi.-.pi.

Interactions. Journal of the American Chemical Society.

Vol. 112, No.14, pp 5525–5534.

Johnstone, A., 2005. Gout The Disease And Non‐Drug Treatment. Hospital

Pharmacist. Vol. 12, pp. 391‐394.

Kelley, WN. & Thomas, DP. 1991. Gout and Other Disorder of Purine

Metabolism. Principle of Internal Medicine. New York: Mc. Graw

Hill, Inc. Hal: 1834-1841

Lemke,T.L., Williams,D.A., Roche, V.F. & Zito, S.W. eds 2008. Foye’s

Principles of Medicinal Chemistry. 6th ed., Baltimore : Lippincott

Williams and Wilkins.

Lin, C. M, Chien, S. C, Chien, T.C, Yu, C.L, & Jen, K.L. Molecular modeling of

flavonoids that inhibits xanthine oxidase. Biochemical and

Biophysical Research Communications 294 (2002) 167–172

Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. 2001.

Experimental and computational approaches to estimate solubility and

permeability in drug discovery and development settings. Advanced

Drug Delivery Reviews 46 (2001) 3–26.

Liu, X.C, Chun, Q.B, Qi, Z.L, & Zhi, L.L. 2014. Evaluation of nematicidal

activity of the essential oil of Homalomena occulta (Lour.) Schott

rhizome and its major constituents against Meloidogyne incognita

(Kofoid and White) Chitwood. Journal of Entomology and Zoology

Studies, 2 (4): 182-186

MacDonal, A.J, Neil, P., Hannah J., and Thierry, L. 2004. Modelling &

Simulation of Pharmacokinetic and Pharmacodynamic Systems -

Approaches in Drug Discovery. The Chemical Theatre of Biological

Systems, PMID : 228681485

Megantara S., Mustarichie R., Warya S., Moektiwardoyo M., & Saputri F. A.,

2014. Docking, Absorption, Distribution, Metabolism and Toxicity

69

Prediction of Anticancer Compounds Found in Plants. World Journal

of Pharmacy and Pharmaceutical Sciences. Vol. 3 No. 10, pp. 72-90.

Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell,

D. S. and Olson, A. J. (2009) Autodock4 and AutoDockTools4:

automated docking with selective receptor flexiblity. J. Computational

Chemistry 2009, 16: 2785-91.

Muchtaridi, Muchtaridi, Dermawan, D., Yusuf, M. 2018. Molekular Docking, 3D

Structure-Based Pharmacophore Modeling, and ADME Prediction of

Alpha Mangostin and its Derivatives against Esterogen Receptor Alpha.

J Young Pharm, 2018; 10(3): 252-259. DOI: 10.5530/jyp.2018.10.58

Muegge, I., Heald, S. L. & Brittelli, D. 2001. Simple selection criteria for drug-

like chemical matter. J. Med. Chem. 44, 1841–1846. DOI:

10.1021/jm015507e

Murray, Rodwell. 2006. Terjemahan Oleh dr. Brahm U (Pendit). Biokimia

Harper Edisi 27. Jakarta: Buku Kedokteran EGC

Nature. 2007. A Decade of Druglikeness. Nature Publishing Group. Vol.6.

November 2007.853

Nugroho, Agung Endro. 2015. Farmakologi : Obat-obat Penting dalam

Pembelajaran Ilmu Farmasi dan Dunia Kesehatan. Jogjakarta :

Pustaka Pelajar.

Owen, L. Patrick dan Johns, Timothy. 1998. Xantin Oksidase Inhibitory Activity

of Northeastern North American Plant Remedies Used for Gout.

Journal of Ethnopharmacology. 64. 149–160

Pacher, P., Nivorozhkin, A., Szabó, C., 2006. Therapeutic Effects of Xanthine

Oxidase Inhibitors: Renaissance Half a Century after the Discovery of

Allopurinol, Pharmacological. Vol.58 , No. 1,pp. 87–114.

Pujiastuti, WM., Sanjaya, MG., 2017. Penentuan Aktivitas Senyawa Turunan

Mangiferin Sebagau Antidiabetes Pada Diabetes Mellitus Tipe 2 Secara

In Silico. UNESA Journal of Chemstry. Vol.6, No. 3, pp. 175.

Rachmania, R.A., Supandi, Larasati, O.A. 2015. Analisis In Silico Senyawa

Diterpenoid Lakton Herba Sambiloto (Andrographis paniculata Nees)

70

pada Reseptor Alpha-gluksidase sebagai Antidiabetes Tipe II.

PHARMACY Vol. 12 No. 2.

Ramdhani T. 2004. Isolasi dan Identifikasi Senyawa Bioaktif Seledri (Apium

graveolens) Dalam Menghambat Aktivitas Xantin oksidase. Skripsi.

Bogor: Institut Pertanian Bogor

Ratih, H., Hartyana, T., dan Farhan., 2014. Pengaruh Pembentukan Ko-Kristal

Alopurinol dengan Asam Benzoat atau D-Asam Tartrat terhadap

Kelarutan dan Laju Disolusinya Fikri Alatas. Cimahi Indonesia

,Universitas Jenderal Achmad Yani.

Rayan, B., Rayan, A., 2017. Avogadro Program for Chemistry Education: To

What Extent can Molecular Visualization and Three-dimensional

Simulations Enhance Meaningful Chemistry Learning. World Journal

Of Chemical Education. Vol. 5, No. 4, pp. 138,140.

Samy, E.M., Hassan, M.A., Tous, S.S., Rhodes, C.T., Improvement of

Availability of Allopurinol from Pharmaceutical Dosage Forms I:

Suppositories. European Journal of Pharmaceutics and

Biopharmaceutics. Vol. 49, pp. 119-127.

Sharma, Rakesh. 2012. Enzyme Inhibition : Mechanism and Scopes. India

Schlesinger, N., 2011. Difficult-to-Treat Gouty Arthritis A Disease

Warranting Better Management., USA, University of Medicine and

Dentistry of New Jersey.

Schottel, B.L., Chifotides, H.T., dan Dunbar, K.R., 2008. Anion-π

interactions. Chemical Society Reviews. Vol.37, No 1, pp. 68–83.

Schumacher, H.R., Chen, L.X., 2008. Gout and Others Crystal-Associated

Arthropathies in Harrison’s Principle of InternalMedicine 17th

Edition, The McGraw Hill, USA, p. 2165.

Siswandono & Soekardjo, B., 2000. Kimia Medisinal. Surabaya, Airlangga

Universitas Press.

Sudoyo, AW, Setiyohadi B, Alwi I, Simadibrata M, Setiati S. Buku Ajar Ilmu

Penyakit Dalam Jilid III edisi V. Jakarta: Interna Publishing; 2014.

71

Syahputra, G., Ambarsari, L., Sumaryada, T., 2014. Simulasi Docking

Kurkuminenol Bisdemetoksikurkumin dan Analognya Sebagai Inhibitor

Enzim 12-Lipoksigenase. Jurnal Biofisika Vol. 10 No. 1.

Tehupeiory., 2006. Artritis Gout dalam Buku Ajar Ilmu Penyakit Dalam,

FKUI, Jakarta, hal. 1208-1210.

Teif VB (October 2005). Ligan-induced DNA condensation: choosing the model".

Biophysical Journal, 89 (4): 2574–87. Bibcode:2005BpJ....89.2574T.

doi:10.1529/biophysj.105.063909. PMC 1366757. PMID 16085765.

Teif VB, Rippe K . 2010. Statistical-mechanical lattice models for protein-DNA

binding in chromatin. Journal of Physics, 22 (41): 414105.

arXiv:1004.5514. Bibcode:2010JPCM...22O4105T. doi:10.1088/0953-

8984/22/41/414105. PMID 21386588.

Umamaheswari, M, K. Asokkumar, A. T. Sivashanmugam, A. Remyaraju. 2009.

In vitro xanthine oxidase inhibitory activity of the fractions of Erythrina

stricta Roxb. Journal of Ethnopharmacology, 124 (2009) 646-648.

Ursu, Oleg., Anwar Rayan., Amiram Goldblum., Tudor I. Oprea. 2011.

Understanding drug-likeness. WIREs Computational Molecular

Science. DOI: 10.1002/wcms.52

Veber, D. F. Stephen R. Johnson. Hung-Yuan Cheng. Brian R. Smith. Keith W.

Ward. Kenneth D. Kopple. 2002. Molecular properties that influence

the oral bioavailability of drug candidates. J. Med. Chem. 45, 2615–

2623. DOI: 10.1021/jm020017n

Wang, Yi-Fen dkk. 2007. Three New Sesquiterpenoids from the Aerial Parts of

Homalomena occulta. Chemistry & Biodiversity, Vol. 4 (2007).

Weaver., 2008, Epidemiology of Gout, Cleveland Clinic Journal of Medicine.

Vol. 75, No. 5, pp. S9-S10.

Waterbeemd, Van. De, H., Carter, R.E., Grassy, G., Kubinyi, K., Martin, Y.C.,

Tute, M.S., Willett, P., 1997. Glossary of Terms Uses in Computational

Drug Design (IUPAC Recommendations 1997), P 1137. WHO. 2002.

Weininger, David. 1987. SMILE, a Chemical Language and Information System.

J. Chem. Inf. Comput. Sci., Vol. 28, No. 1, 1988.

Worcester, M.E. 2008. Nephrolithiasis. NIH Public Acces, Vol. 35(2): 369-vii.

72

Xie, X.Y., Rui, W., Yan, P.S. 2012. Sesquiterpenoids from the Rhizomes of

Homalomena occulta. Planta Med., Vol.78, p 1010-1014.

Yanti, R.A., Sri, T.R., dan Resta D.S. 2016. Uji Aktivitas Penghambatan Xantin

Oksidase secara In-Vitro oleh Isolat 6,4-Dihidroksi-4-

Metoksibenzofenon-2-O-β-D Glukopiranosida(C20H22O10) yang

Diisolasi dari Mahkota Dewa (Phaleria macrocarpa (Scheff.) Boerl).

Pharm Sci Res ISSN 2407-2354, April 2016 (Vol. 3 No. 1)

Zhou, C. M, Yao, C, Sun, HL, Qin, S.X, Gu, G.Y., 1991. Volatile Constituents of

the Rhizome of Homalomena occulta. Planta Med, 57, 391.

Zhao Jie dkk. 2014. A new sesquiterpenoid from the rhizomes of Homalomena

occulta. Formerly Natural Product Letters, 28:20,1669-1673,

DOI:10.1080/14786419.2014.934238

Zeng, Ling-Bin dkk. 2011. Antioxidant activity and chemical constituents of

essential oil and extracts of Rhizoma Homalomenae. Food Chemistry,

125 (2011) 456- 463

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