Cryptocarya densiflora Blume (Lauraceae) is an evergreen tree widely distributed throughout the hills and mountain forests up to 1500 m in Malaysia and Indonesia. The plant has been reported to contain phenanthroindolizidine-type of alkaloids. In the present work, a new phenanthroindolizidine alkaloid named ( R)-13a α-densiindolizidine, was isolated from the dichloromethane (DCM) extract of the leaves. The structure of the alkaloid was established based on 1D and 2D nuclear magnetic resonance (NMR) and liquid chromatography mass spectrometry-ion trap-time of flight (LCMS-IT-TOF) analysis. ( R)-13a α-densiindolizidine displayed binding interactions with crucial amino acid residues in the active sites ofsevere acute respiratory syndrome coronavirus 2 Mpro (SARS-CoV-2 Mpro) and RNA-dependent protease (RdRp) in silico, whilst fulfilling theabsorption, distribution, metabolism, excretion, and toxicity (ADMET) criteria and Lipinsky's rule, thus revealing its potential as a lead compound.
In this study, a set of 72 styryl lactone compounds reported from Goniothalamus species were docked against envelope ([Formula: see text]), NS2B/NS3, NS5 methyltransferase (MTase), and NS5 RdRp dengue virus (DENV) protein. As a result, compounds 5, 37, 38, and 47 were identified as potential dengue protease inhibitors based on minimal docking energy values and multiple interactions with binding sites. The results from in-silico Lipinski’s rule and ADMET analysis showed that these compounds were predicted to fulfil the drug-likeness properties. These ligands were found to fit in well and remain stable in the binding site of the envelope protein, NS2B/NS3, NS5 MTase, and NS5 RdRp. The results from molecular dynamic (MD) simulations indicate that the ligand–protein complex of compound 37 with NS5 MTase was stable throughout the MDs simulations and could interact with essential amino acids within the active sites.
In this study, a set of 234 chemical constituents reported from Goniothalamus species were docked against envelope (E), NS2B/NS3, NS5 methyltransferase, and NS5 RdRp dengue virus (DENV) protein. As the result, compounds 95, 96, 97, 100, 149, 155, and 187 were identified as potential dengue protease inhibitors based on minimal docking energy values and multiple interactions with binding sites. The results from in-silico Lipinski’ rule and ADMET analysis showed that compound 149 was predicted as the most potential compound that fulfills the drug-likeness properties. Ligand 149 was found to be able to fit in well and remain stable in the binding site of proteins envelope, NS2B/NS3, NS5 methyltransferase and NS5 RdRp. The results from molecular dynamic simulations indicate that the ligand-protein complex of 149 in NS5 methyltransferase showed the most preferable, successfully interacted within the active sites and were able to reach convergence within 100 ns.
In our continuing search for bioactive compounds in Goniothalamus lanceolatus, we scrutinized the chemical constituents present in the leaves of this plant. As these leaves are traditionally used to repel mosquitoes, we were inspired to examine the plant for potential anti-dengue activity. Our preliminary screening showed that at a concentration of 50 µg/ml, the dichloromethane extract of these leaves was able to inhibit 90.9% of Dengue Virus Type-2 (DENV-2). Dosedependent plaque assays gave an IC50 of 4.16 µg/ml with a selectivity index (SI) of 5.82. Thus, this extract was selected for in-depth phytochemical analysis. This paper reports an efficient chemical profiling of the G. lanceolatus leaf dichloromethane extract using high-resolution mass spectrometry (UHPLC-ESI-Orbitrap), via data-dependent MS/MS experiments. We used MZmine2 software version 2.50 (MZmine2) for data processing and peak deconvolution. The dereplication strategy began with the determination of molecular formula from accurate mass measurements (m/z). Data mining using MZmine2 followed by cross-search filters against the Dictionary of Natural Products (DNP) produced several hits consisting of styryl-lactones, alkaloids, and acetogenins. A further search of the molecular formula of isolated compounds from different parts of G. lanceolatus using an in-house library unambiguously identified seven compounds including goniolanceolatin A, goniolanceolatin E, (6S,7S,8S)-goniodiol, 1S,5S,7R,8S,3-exo,7-endo-(+)-8-epi-9-deoxygoniopypyrone, goniofupyrone B, parvistone D, and deoxygoniopypyrone B.
RNA-dependent RNA polymerase (RdRp) enzyme is an attractive drug target to treat dengue infection. Nucleoside analogues (Tan et al. 1996).RdRp DENV terletak di kawasan terminal-C NS5 dan mempunyai tiga subdomain yang dinamakan sebagai tapak tangan, jari dan ibu jari (Malet et al. 2008). Subdomain tapak tangan mengandungi tapak aktif dan terdiri daripada dua benang-β tidak selari yang dikelilingi oleh lapan helix-α. Dua motif utama iaitu motif A (Asp533) dan motif C (Asp663) memainkan peranan penting dalam mekanisme pemangkin oleh enzim ini (Steitz 1998). Subdomain jari pula terdiri daripada dua hujung jari dan teras. Salah satu daripada hujung jari mempunyai motif F yang menyediakan tapak pengikat nukleotida trifosfat (NTP) dalam replikasi RNA (Bruenn 2003). Motif E yang berperanan sebagai perangsang sediaan NTP terkandung di dalam subdomain ibu jari (Adachi et al. 2002).
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