Phytochemical and pharmacological profile of genus shorea: A review of the recent literature.

In tropical Southeast Asia, Shorea is the most economically important tree and the largest genus in the Dipterocarpaceae family. It comprises about 150-200 species, of which majority are distributed in Malaysia, with others found in Sumatra and Borneo (Kalimantan) in Indonesia. Research on the chemical constituents of Shorea plants has been ongoing for many years. To date, a total of 113 different compounds, including 83 stilbenes and their resveratrol oligomers, 18 triterpenes/terpenoids, 7 coumarins 3 flavonoids and 2 steroids have been isolated and successfully elucidated from 26 different species of this genus. The diversity of the stilbene resveratrol oligomers in the Shorea genus is primarily due to the difference in the amount of resveratrol constituent units, which include dimers, trimers and tetramers. In addition to the species' traditional usage in the treatment of illnesses, such as diarrhea, toothaches, skin diseases, ear troubles and wounds, the extracts and secondary metabolite compounds isolated from various parts of the plant species are known to have a very potent antioxidant, antimicrobial, anticancer, anti-diabetic, anti-obesity, antiulcer, hepatoprotective and nephroprotective activities. This review aims to summarize the most recent research made from 1999 to date on the secondary metabolite compounds isolated from different species of genus Shorea, as well as the bioactivity (in vitro and in vivo) of the crude extracts and the isolated secondary metabolite compounds.

Structure-based approach: molecular insight of pyranocumarins against α-glucosidase through computational studies.

α-glucosidase is an enzyme that catalyzes the release of α-glucose molecules through hydrolysis reactions. Regulation of this enzyme can increase sugar levels in type-2 diabetes mellitus (DM) patients. Pyranocoumarin derivatives have been identified as α-glucosidase inhibitors. Through an in silico approach, this work studied the inhibition of three pyranocoumarin compounds against the α-glucosidase at the molecular level. Molecular docking and molecular dynamics simulation were performed to understand the dynamics behavior of pyranocoumarin derivatives against α-glucosidase. The prediction of free binding energy (ΔG bind) using the Quantum Mechanics/Molecular Mechanics-Generalized Born (QM/MM-GBSA) approach for each system had the following results, PC1-α-Glu: -13.97 kcal mol-1, PC2-α-Glu: -3.69 kcal mol-1, and PC3-α-Glu: -13.68 kcal mol-1. The interaction energy of each system shows that the grid score, ΔG bind, and ΔG exp values had a similar correlation, that was PC1-α-Glu > PC3-α-Glu > PC2-α-Glu. Additionally, the decomposition energy analysis (ΔG residue bind) was carried out to find out the contribution of the key binding residue. The results showed that there were 15 key binding residues responsible for stabilizing pyranocumarin binding with criteria of ΔG residue bind < -1.00 kcal mol-1. The evaluation presented in this work could provide information on the molecular level about the inhibitory efficiency of pyranocoumarin derivatives against a-glucosidase enzyme based on computational studies.

Nano Uncaria gambir as Chemopreventive Agent Against Breast Cancer.

Background: Breast cancer is one of the main causes of death in women. Uncaria gambir is an Indonesian herbal plant that can be used as an anti-cancer. However, herbal medicines have low bioavailability, which affects their bioactivity. Nanoencapsulation can increase bioavailability and stability of bioactive compounds in herbal medicines. Purpose: This recent finding tried to unravel anti-cancer and chemopreventive of U. gambir nano-encapsulated by Na-alginate. Study Design: U. gambir bioactive compounds were isolated and characterized using UV-Vis spectrometer, FTIR, NMR and HR-MS. U. gambir extract was nanoencapsulated using Na-alginate. Anti-cancer effect was assessed by MTT assay towards T47D cell. Meanwhile, a chemopreventive analysis was carried out in breast cancer mice-induced benzo[α]pyrene. The healthy mice were divided into 8 groups comprising control and treatment. Results: Elucidation of U. gambir ethyl acetate extract confirmed high catechin content, 89.34% (w/w). Successful nanoencapsulation of U. gambir (G-NPs) was indicated. The particle size of G-NPs was 78.40 ± 12.25 nm. Loading efficiency (LE) and loading amount (LA) of G-NPs were 97.56 ± 0.04% and 32.52 ± 0.01%, respectively. G-NPs had an EC50 value of 10.39 ± 3.50 µg/mL, which was more toxic than the EC50 value of extract towards the T47D cell line. Administration of 200 mg/kg BW G-NPs to mice induced by benzo[α]pyrene exhibited SOD and GSH levels of 13.69 ng/mL and 455.6 ng/mL. In addition, the lowest TNF-α level was 27.96 ng/mL. A dose of 100 mg/kg BW G-NPs could best increase CAT levels by 7.18 ng/mL. There was no damage or histological abnormalities found in histological analysis of the breast tissue in the group given 200 mg/kg BW G-NPs.

3,4,3'-Tri-O-methylellagic acid as an anticancer agent: in vitro and in silico studies.

We report a natural product compound isolated from Syzygium polycephalum known as 3,4,3'-tri-O-methylellagic acid (T-EA) as a candidate drug for cancer treatment. The characterization of the isolated T-EA compound was carried out using various spectroscopic methods. The in vitro evaluation showcased the inhibition activity of T-EA towards the T47D and HeLa cell lines with EC50 values of 55.35 ± 6.28 µg mL-1 and 12.57 ± 2.22 µg mL-1, respectively. Meanwhile, the in silico evaluation aimed to understand the interaction of T-EA with enzymes responsible for cancer regulation at the molecular level by targeting the hindrance of cyclin-dependent kinase 9 (CDK9) and sirtuin 1 (SIRT1) enzymes. T-EA showed a binding free energy towards the SIRT1 protein of ΔG bind (MM-GBSA): -30.98 ± 0.25 kcal mol-1 and ΔG bind (MM-PBSA): -24.07 ± 0.30 kcal mol-1, while that of CDK9 was ΔG bind (MM-GBSA): -29.50 ± 0.22 kcal mol-1 and ΔG bind (MM-PBSA): -25.87 ± 0.40 kcal mol-1. The obtained results from this research could be considered as important information on 3,4,3'-tri-O-methylellagic acid as a drug to treat cervical and breast cancers.

Anticancer potential of ß-sitosterol and oleanolic acid as through inhibition of human estrogenic 17beta-hydroxysteroid dehydrogenase type-1 based on an in silico approach.

The human estrogenic enzyme 17beta-hydroxysteroid dehydrogenase type-1 (HSD17B1) provides biosynthesis regulation of active estrogen in stimulating the development of breast cancer through cell proliferation. The ß-sitosterol is classified as a steroid compound and is actually a type of triterpenoid compound that has a similar structure to a steroid. This similarity provides a great opportunity for the inhibitor candidate to bind to the HDS17B1 enzyme because of the template similarity on the active site. Several in silico approaches have been applied in this study to examine the potential of these two inhibitor candidates. Pharmacokinetic studies showed positive results by meeting several drug candidate criteria, such as drug-likeness, bioavailability, and ADMET properties. A combination of molecular docking and MD simulation showed good conformational interaction of the inhibitors and HSD17B1. Prediction of binding free energy (ΔG bind) using the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) approach shows ΔG bind (kcal mol-1) of C1-HSD17B1: -49.31 ± 0.23 and C2-HSD17B1: -33.54 ± 0.34. Meanwhile, decomposition energy analysis (ΔG residue bind) suggested several key residues that were also responsible for the interaction with inhibitors, such as C1-HSD17B1 (six residues: Leu96, Leu149, Pro187, Met193, Val225, and Phe226) and C2-HSD17B1 (four residues: Ile14, Gly94, Pro187, and Val188). Hopefully, the obtained results from this research could be considered for the mechanistic inhibition of the HSDS17B1 enzyme at molecular and atomistic levels.

Tropical Medicinal Plant Extracts from Indonesia as Antifungal Agents against Candida Albicans.

BACKGROUND: Candida albicans is responsible for a wide range of medical ailments, from harmless cutaneous to life-threatening bloodstream infections. Growing cases of antifungal-drug resistance strains of C. albicans become a rationale to explore and develop novel anti-candida agents. In this paper, we assessed the anti-candida activity of the methanolic extracts of various tropical medicinal plants from Myrtaceae, Poaceae, and Zingiberaceae, commonly used in Indonesia to treat fungal infections. METHODS: Candida albicans strain ATCC 10231 was used as a subject to assess the anti-Candida activities of plant methanolic extracts through disc diffusion assay. Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) were observed. RESULTS: All plant extracts in this study showed antifungal activities against C. albicans. Among them, Cymbopogon citratus, Curcuma xanthorrhiza, Curcuma aeruginosa, and Zingiber officinale var. rubrum showed the lowest MIC and MFC value of 3.8 mg/mL. CONCLUSIONS: The growth inhibition of C. albicans on disc diffusion assay was demonstrated by Z. officinale var. rubrum and C. longa, which were comparable to antifungal nystatin. Further investigation of the chemical constituents of the extracts and the cytotoxicity test is needed to further develop plant-derived anti-candida agents.

A new pyrano coumarin from Clausena excavata roots displaying dual inhibition against α-glucosidase and free radical.

A new pyrano coumarin, identified as excavatin A (1) together with two known compounds nordentatin (2) and binorpocitrin (3) was isolated from the 95% EtOH extract of Clausena excavata. All structures were elucidated by using spectroscopy methods such as extensive NMR and HR-FAB-MS spectrometry. All the isolated compounds were tested on antidiabetes activity by using α-glucosidase inhibition assay and the antioxidant activity by DPPH assay. Compounds 1-3 showed antioxidant activity with IC50 values 0.286, 0.02, 0.278 mM. Among them, 2 exhibited inhibition activity against maltase (IC50 5.45 µM) and sucrase (IC50 43.57 µM). However, compounds (1) and (3) displayed inhibition on yeast α-glucosidase with IC50 values 1.92 and 5.58 mM.[Figure: see text].

The dolabellane diterpenes as potential inhibitors of the SARS-CoV-2 main protease: molecular insight of the inhibitory mechanism through computational studies.

An investigation has been carried out on natural products from dolabellane derivatives to understand their potential in inhibiting the SARS-CoV-2 main protease (3CLpro) using an in silico approach. Inhibition of the 3CLpro enzyme is a promising target in stopping the replication of the SARS-CoV-2 virus through inhibition of the subsite binding pocket. The redocking process aims to determine the 3CLpro active sites. The redocking requirement showed a good pose with an RMSD value of 1.39 Å. The combination of molecular docking and MD simulation shows the results of DD13 as a candidate which had a good binding affinity (kcal mol-1) to inhibit the 3CLpro enzyme activity. Prediction of binding free energy (kcal mol-1) of DD13 using the Molecular Mechanics-Poisson Boltzmann/Generalized Born Surface Area (MM-PB/GBSA) approach shows the results ΔG bind(MM-GBSA): -52.33 ± 0.34 and ΔG bind(MM-PBSA): -43.52 ± 0.42. The key residues responsible for the inhibition mechanism are Hie41, Ser46, Met49, Asn142, Cys145, Hie163, Met165, and Gln189. Additionally, pharmacokinetic prediction recommended that DD13 had promising criteria as a drug candidate. The results demonstrated in this study provide theoretical information to obtain a potential inhibitor against the SARS-CoV-2 main protease.

Exploration of stilbenoid trimers as potential inhibitors of sirtuin1 enzyme using a molecular docking and molecular dynamics simulation approach.

A combination of molecular docking and molecular dynamics simulation (250 ns) has been carried out to study the interaction of stilbenoid trimer compounds with the SIRT1 enzyme as the target protein. SIRT1 expression regulates cellular stress responses that lead to the development of cancer. Redocking showed a good native ligand pose with an RMSD value of 1.40 Å at the receptor active site's coordinates. The molecular docking score uses a grid score functional (kcal mol-1), which shows results of 1NS: 79.56, TS1: -26.83, TS2: -87.77, and TS3: -83.67. The TS2 and TS3 candidates were chosen for further analysis because they had a lower grid score than the native ligand (1NS). Furthermore, prediction of binding free energy (kcal mol-1) using the Quantum Mechanics/generalized Born Surface Area (QM/MM-GBSA) method shows the results of 1NS: -31.52 ± 0.39, TS2: -58.99 ± 0.34, and TS3: -43.38 ± 0.35. These results indicate that the TS2 and TS3 compounds have good potential as inhibitors of the SIRT1 enzyme. Additionally, the amino acid residues were responsible for the inhibition mechanism through hydrogen bond interactions at the molecular level, including ASP22, PHE91, PRO11, ILE165, ASP166, and VAL230. The observations made in this study provide theoretical information for exploring the stilbenoid trimers as anticancer agents by targeting the SIRT1 enzyme.

Potential of diterpene compounds as antivirals, a review.

Viruses cause widely transmitted diseases resulting in pandemic conditions. Currently, the world is being hit by the Covid-19 pandemic caused by the SAR-CoV-2 infection. Countries in the world are competing to develop antivirals to overcome this problem. Diterpene compounds derived from natural ingredients (plants, corals, algae, fungi, sponges) and synthesized products have potential as antivirals. This article summarizes the different types of diterpenes such as daphnane, tiglilane, kaurane, abietane, pimarane, labdane, dollabelane, jatrophane, dolastane, prenylated guaiane, tonantzitlolone, casbane, have antivirals activity such as targeting HIV, Coxsackie virus, herpes virus, hepatitis virus, influenza virus, Chikungunya virus, Zika virus, dengue virus, and SARS-CoV. Some compounds such as andrographolide and its derivatives show promising activity in inhibiting the influenza virus. Additionally, compounds such as pineolidic acid, forskolin, sugiol, and many other diterpene compounds showed anti-SAR-CoV activity. The diterpene compound class's high antivirals potential does not rule out the possibility that these compounds can also act as anti-SAR-CoV-2 drugs in the future.

Isolation and identification of a flavonoid compound and in vivo lipid-lowering properties of Imperata cylindrica.

Cogon grass (Imperata cylindrica/I. cylindrica) of the Gramineae family is found abundantly in nature, and the roots of this plant possess several beneficial biological properties. The present study aimed to isolate and identify flavonoid compounds from cogon grass roots and examine their potential as hypocholesterolemic agents. The flavonoid compound was isolated using a maceration method, followed by gravity column chromatography until a pure compound was obtained. The molecular structure of the isolated compound was determined using 1H-nuclear magnetic resonance (NMR) and 13C-NMR spectroscopy. An in vivo lipid-lowering test used a randomized post-test only control group experimental design in rats with hypercholesterolemia. The animals were divided into four groups: K0, negative control; K1, positive control; K2, ethanol extract treated group; and K3, ethyl acetate fraction treated group, and the lipid profiles were examined at the end of the study. The isolated compound, 7,3',5'-trimethoxyflavonol, was collected in yellow powder form; was shown to be a flavonoids and was comprised of 18 carbon atoms and 16 hydrogen atoms. In vivo tests demonstrated that 15 mg/200 g body weight (BW) of an ethanol extract significantly lowered total cholesterol levels (P=0.001) but did not lower low-density lipoprotein (LDL) (P=0.109) and high-density lipoprotein (HDL) levels (P=0.003). The fraction of ethyl acetate administered at 15 mg/200 g BW was capable of lowering the total cholesterol levels significantly (P=0.002) and lowered LDL levels (P=0.006) but was unable to increase HDL levels (P=0.190). The in vivo tests showed that the ethyl acetate fraction of I. cylindrica reduced total cholesterol and LDL levels more effectively than the ethanol extract, but did not affect HDL levels in rats with hypercholesterolemia.

In silico approach: biological prediction of nordentatin derivatives as anticancer agent inhibitors in the cAMP pathway.

A combination of computational techniques has been carried out to predict the binding of nordentatin derivatives based on pyranocoumarin semi-synthesis with the target protein from the expression of the PDE4B gene. The inhibition of the cAMP pathway is the main target of anti-cancer drugs, which is responsible for uncontrolled cell division in cancer. Modeling was done using a combination of semi-empirical methods and the density functional theory (PM3-DFT/6-31G*/B3LYP) to obtain the optimal structure of a small ligand that could be modeled. Studies on the interaction of the ligands and amino acid residues on protein targets were carried out using a combination of molecular docking and molecular dynamic simulation. Molecular docking based on functional grid scores showed a very good native ligand pose with an RMSD of 0.93 Å in determining the initial coordinates of the ligand-receptor interactions. Furthermore, the amino acid residues responsible for interaction through H-bonds were Tyr103, His104, His177, Met217, and Gln313. The binding free energy (kcal mol-1) results of the candidates were PS-1 (-36.84 ± 0.31), PS-2 (-35.34 ± 0.28), PS-3 (-26.65 ± 0.30), PS-5 (-42.66 ± 0.26), PS-7 (-35.33 ± 0.23), and PS-9 (-32.57 ± 0.20), which are smaller than that of the native ligand Z72 (-24.20 ± 0.19), and thus these have good potential as drugs that can inhibit the cAMP pathway. These results provide theoretical information for the efficient inhibition of the cAMP pathway in the future.

Review: Secondary Metabolites of Aquilaria, a Thymelaeaceae Genus.

BACKGROUND: Aquilaria, a genus belonging to the Thymelaeaceae, produces fragrant resinous agarwood, also known as eaglewood, which has been used as incense since old times. The intense fra-grance is the result of the presence of a wide variety of secondary metabolites. OBJECTIVE: This genus was reported contained sesquiterpenes, chromones, flavonoids, benzophenones, diterpenoids, triterpenoids, and lignans. CONCLUSION: Here, we review the different secondary metabolites that have been identified in Aquilaria to show their diversity and to allow comparison with other Thymelaeaceae genera.