Lung cancer has a high prevalence, with a growing number of new cases and mortality every year. Furthermore, the survival rate of patients with non-small-cell lung carcinoma (NSCLC) is still quite low in the majority of cases. Despite the use of conventional therapy such as tyrosine kinase inhibitor for Epidermal Growth Factor Receptor (EGFR), which is highly expressed in most NSCLC cases, there was still no substantial improvement in patient survival. This is due to the drug’s ineffectiveness and high rate of resistance among individuals with mutant EGFR. Therefore, the development of new inhibitors is urgently needed. Understanding the EGFR structure, including its kinase domain and other parts of the protein, and its activation mechanism can accelerate the discovery of novel compounds targeting this protein. This study described the structure of the extracellular, transmembrane, and intracellular domains of EGFR. This was carried out along with identifying the binding pose of commercially available inhibitors in the ATP-binding and allosteric sites, thereby clarifying the research gaps that can be filled. The binding mechanism of inhibitors that have been used clinically was also explained, thereby aiding the structure-based development of new drugs.
Five known porphyrins, 5,10,15,20-tetrakis(p-tolyl)porphyrin (TTP), 5,10,15,20-tetrakis(p-bromophenyl)porphyrin (TBrPP), 5,10,15,20-tetrakis(p-aminophenyl)porphyrin (TAPP), 5,10,15-tris(tolyl)-20-mono(p-nitrophenyl)porphyrin (TrTMNP), 5,10,15-tris(tolyl)-20-mono(p-aminophenyl)porphyrin (TrTMAP), and three novel porphyrin derivatives, 5,15-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-10,20-di(p-tolyl)porphyrin (DBECPDTP), 5,10-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-15,20-di-(methylpyrazole-4-yl)porphyrin (cDBECPDPzP), 5,15-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-10,20-di-(methylpyrazole-4-yl)porphyrin (DBECPDPzP), were used to study their interaction with protein targets (in silico study), and were synthesized. Their cytotoxic activities against cancer cell lines were tested using 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolium bromide (MTT) assay. The interaction of porphyrin derivatives with carbonic anhydrase IX (CAIX) and REV-ERBβ proteins were studied by molecular docking and molecular dynamic simulation. In silico study results reveal that DBECPDPzP and TrTMNP showed the highest binding interaction with REV- ERBβ and CAIX, respectively, and both complexes of DBECPDPzP-REV-ERBβ and TrTMNP-CAIX showed good and comparable stability during molecular dynamic simulation. The studied porphyrins have selective growth inhibition activities against tested cancer cells and are categorized as marginally active compounds based on their IC50.
ABSTRAKBakteri yang resisten terhadap antibiotik menimbulkan ancaman serius, sehingga diperlukan obat alternatif untuk mengganti dengan beralih ke bahan alam yang ketersediaannya melimpah di Indonesia, salah satunya adalah madu. Madu "Manuka" dilaporkan efektif mengatasi infeksi kulit yang sudah resisten terhadap antibiotik serta efektif untuk gangguan pencernaan, sehingga fakta tersebut telah mendorong dilakukannya penelitian untuk menguji dan membuktikan efek antibakteri madu jenis lainnya. Pada penelitian ini, enam madu asli lebah, asal Indonesia diuji aktivitas antibakterinya terhadap strain Staphylococcus aureus mewakili golongan bakteri Gram positif dan strain Escherichia coli mewakili golongan bakteri Gram negatif. Diawali pengumpulan dan penyiapan enam sampel madu uji, kemudian diuji secara organoleptik dan uji fisikokimia untuk menentukan mutu dari madu, meliputi uji aktivitas enzim diastase, hidroksimetilfurfural (HMF) dan kadar air yang dilakukan untuk menguji apakah madu yang diuji asli asal lebah dan dalam kualitas yang baik. Selanjutnya dilakukan pengujian aktivitas antibakteri madu asli lebah tersebut terhadap bakteri penyebab infeksi saluran pernapasan yang diwakili oleh Staphylococcus aureus yang merupakan bakteri Gram positif dan bakteri penyebab infeksi saluran pencernaan yang diwakili oleh Escherichia coli yang merupakan bakteri Gram negatif, menggunakan metode difusi agar perforasi. Uji organoleptik yang dilakukan terhadap enam sampel madu asli lebah, asal Indonesia (S1, S2, S3, S4, S5, S6) memberikan hasil yang memenuhi persyaratan mutu madu yang baik. Hasil pengujian enzim diastase dan uji kadar air memenuhi persyaratan SNI 3545:2013 tentang madu. Hasil uji HMF tidak memenuhi syarat, pada sampel S1 dan S6 karena HMF melebihi kadar yang dipersyaratkan. Sampel S1 dan S6 memberikan kadar HMF berturut-turut 62,22 mg/kg dan 50,97 mg/kg, sehingga tidak memenuhi persyaratan kadar HMF maksimum 50% b/b. Uji aktivitas antibakteri madu dengan konsentrasi 100% terhadap bakteri Staphylococcus aureus memberikan diameter hambat 21,33 mm pada sampel S4, menunjukkan kategori antibakteri sangat kuat, karena masuk dalam kisaran 20-35 mm, sedangkan pengujian terhadap bakteri Escherichia coli pada sampel S4 memberikan diameter hambat 19,67 mm termasuk kategori antibakteri kuat karena masuk dalam kisaran 10-20 mm.
Due to their ability to inhibit cyclooxygenase-2 (COX-2), certain flavonoids show anti-inflammatory effects. Quercetin is a flavonoid suitable to be chosen as the lead compound for development of safe anti-inflammatory agent, because in addition to its anti-inflammatory effect, quercetin shows also protective effect in gastrointestinal track. The objective of this research is to study the binding modes of certain flavonoids and predict the quercetin derivatives inhibiton activity on COX-2 by means of docking method using ArgusLab 4.0.1 software. Some flavonoids (7-hydroxyflavone, apigenin, galangin, kaempferol, quercetin, naringenin and daidzein) and quercetin derivatives were used as ligands for docking study. The COX-2 structure was obtained from Brookhaven protein databank. After assigning hydrogen atoms and charges, computational docking was performed. The docking results were evaluated based on the binding energy and hydrogen bonding of the ligands on binding site of COX-2. A curve constructed by plotting binding energy versus logarithm of IC50 of flavonoids shows a good correlation with a regression equation of log IC50 = 0.8069 ΔGbind + 9.4456 (r = 0.9226; P
A series of cationic porphyrin-anthraquinone hybrids bearing either pyridine, imidazole, or pyrazole rings at the meso-positions have been investigated for their interaction with DNA G-quadruplexes by employing molecular docking and molecular dynamics simulations. Three types of DNA G-quadruplexes were utilized, which comprise parallel, antiparallel, and mixed hybrid topologies. The porphyrin hybrids have a preference to bind with parallel and mixed hybrid structures compared to the antiparallel structure. This preference arises from the end stacking of porphyrin moiety following G-stem and loop binding of anthraquinone tail, which is not found in the antiparallel due to the presence of diagonal and lateral loops that crowd the G-quartet. The binding to the antiparallel, instead, occurred with poorer affinity through both the loop and wide groove. All sites of porphyrin binding were confirmed by 6 ns molecular dynamics simulation, as well as by the negative value of the total binding free energies that were calculated using the MMPBSA method. Free energy analysis shows that the favorable contribution came from the electrostatic term, which supposedly originated from the interaction of either cationic pyridinium, pyrazole, or imidazole groups and the anionic phosphate backbone, and also from the van der Waals energy, which primarily contributed through end stacking interaction.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.