AKAR KUNING (Arcangelisia flava) SEBAGAI INHIBITOR EGFR : KAJIAN IN SILICO

Akar kuning (Arcangelisa flava) diketahui memiliki berbagai aktivitas farmakologi seperti antikanker. Beberapa metabolit sekunder akar kuning menunjukkan aktivitas antiproliferasi sel kanker. Overproliferasi pada sel kanker salah satunya disebabkan oleh kelainan pada EGFR, kelompok reseptor yang berperan pada saat inisiasi proliferasi sel. Inhibisi pada EGFR dapat menghambat proses proliferasi sel kanker. Penelitian ini bertujuan mengetahui metabolit sekunder dari akar kuning dengan potensi paling besar sebagai inhibitor berbagai EGFR. Metode yang digunakan adalah molecular docking beberapa metabolit sekunder akar kuning terhadap EGFR-1, EGFR-2, EGFR-3, dan EGFR-4. Hasil docking menunjukkan berberin memberikan energi bebas ikatan paling negatif dan konstanta inhibisi paling kecil pada seluruh EGFR, dengan afinitas paling tinggi ditunjukkan pada EGFR-2 dengan ΔG dan ki secara berturut-turut sebesar -9,34 kcal/mol dan 141,81 nM. Over-ekspresi aktivitas dari EGFR-2 sendiri seringkali terjadi pada kanker payudara, terutama kanker payudara HER2-positif. Hasil tersebut memberikan prediksi bahwa berberin memiliki aktivitas sebagai inhibitor EGFR terutama EGFR-2 dan berpotensi untuk dikembangkan pada terapi kanker payudara HER2-positif. Keyword : Akar Kuning, EGFR, Antikanker, Dockin

BETWEEN ARTEMISININ AND DERIVATIVES WITH NEURAMINIDASE: A DOCKING STUDY INSIGHT

Objectives: This study aims to find the relationship between artemisinins and neuraminidase (NA) with molecular docking study and also to determine the most potent NA inhibitor from artemisinin and derivatives.Methods: All ligands were sketched and optimized using Gaussian 03W with Hartree-Fock method basis sets 6-311G. Molecular docking was performed using AutoDock 4.2.3 toward NA in complexes with oseltamivir as co-crystal ligand. The main parameters used were the free energy of binding (ΔG) and dissociation constant (Ki) as affinity marker.Results: Artesunate provided most negative free ΔG and lowest Ki toward NA with −9.55 kcal/mol and 100.66 nM, respectively. Artesunate shows higher affinity than oseltamivir with interactions between artesunate and amino acids at position 246 had important influences on artesunate affinity toward NA from H5N1.Conclusion: In silico molecular docking results indicated that artesunate could be considered as NA inhibitor and should be potential to be developed as anti-influenza particularly to H5N1 with oseltamivir resistance

CHEMICAL STRUCTURE OPTIMIZATION OF LUPEOL AS ER-Α AND HER2 INHIBITOR

Objectives: Lupeol, a triterpenoid isolated from Kasturi (Mangifera casturi) fruit has been known for having several pharmacological activities, including anticancer properties. Lupeol showed antiproliferative activity toward many cancer cells line including breast cancer. Lupeol showed promising potency as both ER-α and HER2 inhibitors, although still lower than known ER-α and HER2 Inhibitors. Chemical structure optimization of lupeol was predicted could increase the affinity of lupeol derivatives against ER-α and HER2. This study aims to determine lupeol derivative with the highest affinity against ER-α and HER2.Methods: All ligands were sketched and optimized using Gaussian 03W with Hartree–Fock method basis set 3-21G. Molecular docking was performed using Autodock 4.2.6 on several modified chemical structure of lupeol against active site of ER-α and HER2. The main parameter used was the free energy of binding and inhibition constants as affinity marker.Results: The docking results show that lupeol derivative with an amine group (Lupeol-2) and ethyl group (Lupeol-4) at position C3 provide the highest affinity with the free energy of binding and dissociation constant −12.24 kcal/mol and 1.07 nM for ER-α also −9.63 kcal/mol and 86.94 nM for HER2, respectively. Interestingly, although lupeol derivatives showed higher affinity toward ER-α, their amino acid residues were closer to the interaction on HER2.Conclusion: These results predict that lupeol have greater potential to be developed as a HER2 inhibitor. Further, derivate lupeol-4 should be potential to be developed as HER2-positive breast cancer therapy

Studi Docking Molekular Senyawa Turunan Kuinolin Terhadap Reseptor Estrogen-Α

Estrogen-α (ER-α) is the main target for ER + therapy. Inhibition of ER-α is known to slow the proliferation of ER + breast cancer cells. Quinoline derivatives are known to have anticancer activity by inhibiting several types of receptors. It is not known whether quinoline can inhibit ER-α. This study aims to determine the interaction between ER-α with quinoline derivative compounds. Molecular docking of ER-α showed that quinine gave the most negative bond-free energy and the smallest inhibition constant, respectively -8.73 kcal/mol and 0.398 μM. These results provide predictions that quinine has activity as an ER-α inhibitor and has the potential to be developed in the treatment of ER + breast cancer. However, the affinity shown by quinine was lower than that of 4-hydroxytamoxifen, a potent inhibitor of ER-α

In-Vitro Study of Antioxidant Activities from Ethanol Extracts of Akar Kuning (Arcangelisia flava)

This study aims to determine the antioxidant activity of akar kuning (Arcangelisia flava) stem extract from Central Kalimantan using 1,1-diphenyl-2-picrylhydrazyl (DPPH) method. This research includes extraction of simplicia and test of antioxidant activity by DPPH method. Based on the analysis of antioxidant activity on ethanol extract from yellow root plant stem IC50 values of 136.81 ppm were obtained. This IC50 value indicates the antioxidant strength of the yellow root plant stems including in the moderate category. Further research on antioxidant activity in the fraction of akar kuning stems needs to be done to determine the composition of the antioxidant compounds in each solvent

Profile of Thin-Layer Chromatography and UV-Vis Spectrophotometry of Akar Kuning Stem Extract (Arcangelisia flava)

This study aims to obtain the profile of Thin-Layer Chromatography (TLC) and Ultraviolet-Visible (UV-Vis) spectrophotometry from the ethanol extract of akar kuning stems (Arcangelisia flava) from Central Kalimantan. The TLC method is used with the orientation phase of the combination of polar-non-polar solvents resulting from orientation, while ethanol is used as the solvent for UV-Vis spectrophotometers. TLC results showed the formation of three stains on a mixture of polar solvents chloroform : methanol : water while in a non-polar solvent combination n-hexane : ethyl acetate did not show any stains. Comparison of retention factor (Rf) values shows the best combination of polar solvents to separate stains at a ratio of 5 : 2 : 1, respectively. Separation in 2-dimensional TLC with polar solvents showed a similar pattern with 1-dimensional separation in the form of three stains. UV-Vis spectrophotometer results showed four main peaks with wavelength 227.2; 267.4; 345.2; and 425.3 nm, respectively. The profile of the peak formed is very similar to that shown by berberine, one of the primary metabolites of akar kuning. TLC and UV-Vis spectrophotometers profiles obtained are expected to support further research using akar kuning stems, especially those from Central Kalimantan

Introducing a two‐dimensional graph of docking score difference vs. similarity of ligand‐receptor interactions

Observation of molecular docking results was generally performed by analyzing the docking score and the interacting amino acid residues separately either in tables or graphs. Sometimes it was not easy to rank the tested ligands’ docking results, especially if there were many ligands. This study aims to introduce a new way to analyze docking results with a two‐dimensional graph between the difference in docking score and the similarity of ligand‐receptor interactions. Molecular docking was performed with one reference ligand and several test ligands. The docking score difference was obtained between the test and the reference ligands as the graph’s x‐axis. Meanwhile, the y‐axis contains the similarity of ligand‐receptor interactions, obtained from the ratio of amino acid residues and the types of interactions between the test and reference ligands. Docking result analysis was more straightforward because two critical parameters were presented in one graph. This graph could be used to support the analysis of the docking results

ANTIBACTERIAL ACTIVITY OF AKAR KUNING (ARCANGELISIA FLAVA) SECONDARY METABOLITES: MOLECULAR DOCKING APPROACH

Objectives: Akar kuning (Arcangelisia flava) was known to have various pharmacological activities including as antibacterial. Several Gram-positive and Gram-negative bacteria show response to akar kuning secondary metabolites, although the type of metabolites that inhibit the growth of each type of bacteria not yet known. This study aims to obtain the prediction of metabolites from akar kuning with the greatest antibacterial potential against various types of antibacterial receptors.Methods: Molecular docking was performed using Autodock Vina 1.1.2 on several secondary metabolites of akar kuning against active site of several antibacterial receptors that were known for many antibiotics including as cell wall, protein, nucleic acid synthesis inhibitors, and antimetabolites. The main parameter used was the free energy of binding as affinity marker.Results: The docking results show that among 11 metabolites studied, 6-hydroxyfibraurin, berberine, and fibleucin provided the lowest free energy of binding between 11 antibacterial receptors compared with natural substrates or inhibitors from each receptor. Interesting results show by berberine as inhibitor of protein synthesis with possibility of allosteric site discovery. Berberine also shows more than 75% similarity with natural substrate of cell wall inhibition receptor, indicating possible similar type of interaction.Conclusion: Overall, it seems that for the selected secondary metabolites of akar kuning, the main mechanism of action was the inhibition of protein and cell wall synthesis, which was shown by berberine

Pharmacophore Optimization Of Berberine As HER2 Inhibitor

Previous research has shown that berberine, an alkaloid found in several plants such as akar kuning (Arcangelisia flava) shows the potential for inhibition of Human epidermal receptor-2 (HER2). Pharmacophore modification on the berberine was predicted could increase the affinity of berberine derivatives against HER2. The present study aims to determine the main pharmacophore of berberine with the highest influence towards berberine affinity against HER2. Molecular docking was performed on several modified pharmacophore of berberine against HER2. The docking results show that O atom at position number 23 has the most important influence on the berberine affinity towards HER2, where modification of O atom resulting in a decrease of berberine affinity. The highest affinity showed by derivate berberine-6 with the free energy of binding score and dissociation constant -10.80 kcal/mol and 12.17 nM, respectively. In contrast with other berberine derivatives, the berberine-6 derivate does not interact with the amino acid threonine at position 862. It provides a prediction that interaction of that amino acid potentially decrease the berberine activity towards active site of HER2. Further, derivate berberine-6 could be developed into HER2 inhibitor and should be potential to be developed as HER2-positive breast cancer therapy.Penelitian sebelumya menunjukkan bahwa berberin, alkaloid yang terdapat pada beberapa tumbuhan seperti akar kuning (Arcangelisia flava) menunjukkan potensi inhibisi terhadap Human epidermal receptor-2 (HER2). Modifikasi pharmacophore pada struktur kimia berberin diprediksi dapat meningkatkan afinitas derivat berberin terhadap HER2. Tujuan penelitian ini adalah menemukan pharmacophore utama pada berberin yang memiliki pengaruh paling penting terhadap afinitas berberin pada HER2. Metode yang digunakan adalah molecular docking hasil modifikasi pharmacophore terhadap HER2. Hasil docking menunjukkan atom O pada posisi nomor 23 memiliki pengaruh penting terhadap afinitas berberin pada HER2, dimana modifikasi atom O menurunkan afinitas berberin. Afinitas tertinggi ditunjukkan oleh derivat berberin-6 dengan energi bebas ikatan dan konstanta disosiasi secara berturut-turut sebesar -10,80 kcal/mol dan 12,17 nM. Berbeda dengan derivat berberin lainnya, derivat berberin-6 tidak berinteraksi dengan asam amino treonin pada posisi 862. Hal tersebut memberikan prediksi bahwa interaksi pada asam amino tersebut berpotensi menurunkan afinitas berberin terhadap sisi aktif HER2. Lebih jauh derivat berberin-6 dapat dikembangkan menjadi inhibitor HER2 dan berpotensi untuk dikembangkan pada terapi kanker payudara HER2-positif