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Rumput Mutiara/Oldenlandia (Hedyotis corymbosa)

Rumput Mutiara/Oldenlandia (Hedyotis corymbosa (L.] Lamk.)

 

1. Name of Plant

Oldenlandia. This grass have efficacy same as Hedyotis diffusa Willd. = Rumput Iidah ular = Baihua she she cao.

2. Classification of plant

Division: Spermatophyta
Sub Division : Angiospermae
Class : Dicotyledoneae
Order : Rubiales
Family : Rubiaceae
Genus : Hedyotis
Species : Hedyotis corymbosa L

3. Morphology of Plant
The grasses grow scattered shade, little weak, height 15 – 50 cm, grow fertile in the moist soil on the side of the road, roadside ditch, have many branch. Stem-sided, leaves face cross, leaves base short / almost sitting, the length of the leave 2 – 5 cm, pointed tip, bone leave one in the middle. Tip of the leaves have the short hair. The flowers come out from the axillaries, the shape like a white umbrella, form of compound flower 2-5, the stalk of flower (parent) hard like wire, length 5 10 mm. Broken end.

 

4. Chemical Ingredients and benefit

Hentriacontane, stigmasterol, ursolic acid, oleanolic acid, Beta-sitosterol, sitisterol-D-glucoside, p-coumaric acid, flavonoid glycosides (Khastgir et al., 1960), and baihuasheshecaosu (possibility of analog coumarin). Character of plant is sweet taste slightly bitter, soft, neutral, and coldish. Has been known since ancestor to relieve fever and hepatoprotector (Mishra et al., 2009).

 

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Figure : Structure of Ursolic Acid and Oleanolat Acid

 

5. Anticancer Mechanism Research

Oldenlandia is one of plant that has potency as anticancer. Oleanolat acid and ursolic acid, load of this plant could be expected to inhibit cancer.

Anan (2000) reported that hexane extract of oldenlandia have ED50 value amount 30μg/mL, whereas the ethyl acetate extract and methanol extract have ED50 value greater than 30μg/mL. According Sadasivan et al. (2006), work of these compound are blocking the growth of cell cycle in phase G1 that marked by the decrease of protein cyclin expression D1, D2, and E and their active partner like CDK2, 4, and 6 with inducting p21/WAF1.

Research that done by Asyhar (2009) using ethanolic extract of oldenlandia, showing the quantitative observation result using immunohistochemistry against protein expression N-ras known that compound in the ethanolic extract can increase spurring expression of N-ras cell normal so that has prospect as hepatoprotector.

Load of glycoside flavonoid in Oldenlandia can be expected to inhibit the carcinogenesis process in vitro or in vivo. The inhibition happen in initiation level, promotion or progression through molecular mechanism such as inactivation of carcinogen compound, antiproliferative, angiogenesis inhibition, cell cycle arrest, apoptosis induction and antioxidant (Ren et al., 2003). Most of carcinogen compound like Polisiklik Aromatik Hidrokarbon (PAH) need activation by cytochrome P450 forming reactive intermediate before bind to DNA. Covalent bond between DNA with active carcinogen compound cause DNA damage. Flavonoid in this process acts as blocking agent (Watternberg, 1985). Blocking of carcinogen action can through some mechanism such as through inhibiting the activity of isoenzym cytochrome  P450 namely CYP1A1 and CYP1A2 so that non-reactive carcinogen compound. The other mechanism through carcinogen detoxification.

Flavonoid also increase the expression of enzyme Gluthation S-Transferase (GST) that can detoxification the active carcinogen so that can be more polar and eliminated from body.  The other mechanism through active carcinogen bond by flavonoid so that can inhibit the bind with DNA, RNA or protein target (Ren et al., 2003).

Computation Test with Docking Method

Docking has done by ursolat acid and oleanolat acid for knowing inhibition potency against  CDK 2 and CDK 6 with program Molecular Operating Environment (MOE).

Docking result between CDK2 with oleanolat acid produce score -9,6992 that the value is bigger than ursolat acid with CDK2 -10,2436 (table 1). Whereas score for CDK2 with the other comparator ligand namely CDK4 inhibitor is -11,2970, the smallest between the other two interaction. It show that bind between CDK4 inhibitor with CDK2 more stable so that cause inhibitor activity against CDK2 is higher than the other. Benzena group and Lys 409 occurs load transfer interaction. This bind strength is 1-7 kkal/mol. Whereas interaction between oleanolat acid with CDK2 is occur hydrogen bind between O with residue Leu 83. The other hydrogen bonding occurs between atom H in carbonil carboxilate with residue Gln 131 and atom H in group OH with residue Glu 81. This hydrogen bonding has bond strength 1-7 kkal/mol. Interaction between ursolat acid and CDK2 is the existence of hydrogen bonding between group OH with residue amino acid His 84 and Lys 33 as donor proton for group OH in carboxylic. Even between CDK4 inhibitor-CDK2 and oleanolat acid-CDK2 have bond strength that same but the load transfer that happen in group benzene is stronger that hydrogen bonding. Thus, can be predicted that electrostatic bonding effect from group benzene interaction with residue amino acid Lys 409 is greater than total of hydrogen bonding nor strong to weak of hydrogen bonding so that receptor target inhibition (CDK2) by ligand comparison (CDK4 inhibitors) is greater than Oleanolat Acid and Ursolat Acid against protein target CDK2.

Table I. Score result docking ligand test, ligand comparison, and ligand endogen with CDK2
Ligand test Score Ligand Comparison Score Ligan endogen Score
ursolat acid -10,2436 CDK4 inhibitor -11,2970 ATP -18,5398
oleanolat acid -9,6992

If compared with ligand endogen then score that obtainable between ATP-CDK2, the smallest is -18,5398 (table 1). It means that ATP has the highest potency for inhibit CDK2 that can be showed with total and type of both. Group phosphate in ATP is main group that interacted with CDK2. The existence of negative load in group phosphate can forming electrostatic bonding that mutually reinforcing with residue amino acid Lys 129 (figure 1). This electrostatic bonding has a high affinity compared with hydrogen bonding and hydrophobing bonding  because has bond strength 10 kkal/mol. Moreover, also formed hydrogen bonding between -OH and phosphate with Ile 10, Val 264 and Glu 12 that contact with solven.

 

Figure 1. Interaction of Ligand with CDK2. a. Interaction CDK4 inhibitor with CDK2. There is load transfer between group benzene with Lys 409; b. Interaction of oleanolat acid with  CDK2. There is hydrogen bonding between atom O with residue Leu 83, atom H in carbonyl carboxylic with residue Gln 131 and atom H in group OH with residue Glu 81; c. Interaction of ursolat acid with CDK2. There is hydrogen bonding between group OH with residue  amino acid His 84 and Lys 33 as donor proton for group OH in carboxylic; d. Interaction of ATP with CDK2. Group phosphate can forming electrostatic bonding that mutually reinforcing with amino acid residue Lys 129. There is hydrogen bonding between -OH and fosfat with Ile 10, Val 264 and Glu 12 that contact with solven.

Table II. Score result docking ligand test, ligand comparison, and ligand endogen with CDK6

Ligand test Score Ligand Comparison Score Ligan endogen Score
Ursolat Acid -11,0750 Fisetin -14,1650 ATP -15,5637

Oleanolat Acid -11,7745

 

Figure 2. Interaction Ligand with CDK6. a. Interaction of fisetin with CDK6. Glu A31 that hydrogen bond with H in group OH in fisetin; b. Interaction of ursolat acid with CDK6. There is hydrogen bonding between atom H in group OH with residue Val 150, Lys 36 and Thr 38; c. Interaction of oleanolat acid with CDK6. There is hydrogen bonding in atom H in group carboxylic ursolat acid with residue Ala 152; d. Interaction of ATP with CDK6. There is electrostatic bonding that mutually reinforcing between group phosphate with residue Lys 144 and Lys 86. Then hydrogen bonding between atom H in group OH with residue Pro 35 and Lys 36.

Whereas in CDK6-fisetin (Figure 2), interaction that happen is Glu A31 that hydrogen bond with H in group OH in fisetin. Interaction of this ligand-receptor has score -14,1650 (table II). Whereas interaction between ursolat acid with CDK2 is hydrogen bonding between atom H in group OH with residue Val 150, Lys 36 and Thr 38. Then, interaction of oleanolat acid with CDK6 is the existence of hydrogen bonding in atom H in group carboxylic ursolat acid with residue Ala 152. Thus, even in ligand comparison interaction is fisetin with CDK6 only there one hydrogen bonding but the intensity is graeter than interaction of ursolat acid compound with CDK6 that has 3 hydrogen bonding, so that score in ursolat acid with CDK6 is greater than fisetin-CDK6 is -11,0750. Whereas the score in oleanolat acid and CDK6 is -9,6992, so that this inateraction has the smallest interaction.
If compared with ATP, score docking ATP-CDK6 is smaller, that is -18,5398 it means that bonding between ATP and CDK6 more stable. It showed with existence of electrostatic bonding that reinforce between group phosphate with residue Lys 144. Moreover, also there electrostatic bonding between group phosphate with residue Lys 86.  There is also hydrogen bonding between atom H in group OH with residue Pro 35 and Lys 36. Thus, affinity of ATP against CDK6 ia greater bond because ATP is such a endogen compound that has binding site with CDK6.

Contributors : Rifki Febriansah, Aditya Asyhar, Muhammad Iqbal, Adam H and Endang Sulistyorini

Daftar pustaka

Kakizoe and tadao, 2003. ‘Chemoprevention of cancer Focusing on Clinical Trials’, Jpn J. Clin. Oncol. 33(9). 421-442.