Lung cancer was a second common cancer case due to the high cigarette smoking activity both in men and women. One of protein receptor which plays an important role in the growth of the tumor is Epidermal Growth Factor Receptor (EGFR). EGFR protein is the most frequent protein mutation in cancer and promising target to inhibit the cancer growth. In this work, the stability of the hydrogen bond as the main interaction in the inhibition mechanism of cancer will be evaluated using molecular dynamics simulation. There were two compounds (A1 and A2) as new potential inhibitors that were complexed against the EGFR protein. The dynamic properties of each complexed were compared with respect to erlotinib against EGFR. The result revealed that both compounds had an interaction in the main catalytic area of protein receptor which is at methionine residue. Inhibitor A1 showed additional interactions during simulation time but the interactions tend to be weak. Inhibitor A2 displayed a more stable interaction. Following dynamics simulation, binding free energy calculation was performed by two scoring techniques MM/GB(PB)SA method and gave a good correlation with the stability of the complex. Furthermore, potential inhibitor A2 had a lower binding free energy as a direct consequence of the stability of hydrogen bond interaction.
Erlotinib, Afatinib, and WZ4002 are quinazoline derivative compounds and classified as first, second, and third-generation EGFR inhibitor. All inhibitors have been given directly to cancer patients for many years but find some resistance. These three compounds are candidates as the lead compound in designing a new inhibitor. This work aims to design a new potential quinazoline derivative as an EGFR inhibitor focused on the molecular docking result of the lead compound. The research method was started in building a pharmacophore model of the lead compound then used to design a new potential inhibitor by employing the AutoDock 4.2 program. Molecular dynamics simulation evaluates the interaction of all complexes using the Amber15 program. There are three new potential compounds (A1, B1, and C1) whose hydrogen bond interaction in the main catalytic area (Met769 residue). The Molecular Mechanics Generalized Born Surface Area (MM-GBSA) binding energy calculation shows that B1 and C1 compounds have lower binding energies than erlotinib as a positive control, which indicates that B1 and C1 are potential as EGFR inhibitor.
Secondary metabolites isolated from Cryptocarya was known to have various activity especially their cytotoxicity in P388 cell. There were two species of Cryptocarya studied in this research that were Cryptocarya konishii and Cryptocarya lucida. In both species, 8 isolate compounds had bioactivity as anticancer in P388 cells. This study aimed to know the binding affinity and ADMET properties of each isolated compound through P-glycoprotein substrate since this protein was reported to be responsible for the inhibition of P388 cells. Molecular docking was performed using AutoDock4 and AutoDockTools software to know the binding energy and interaction of isolate compounds against the P-glycoprotein substrate. ADMET properties calculation was done using the pkCSM web server for all compounds. Molecular docking results showed that Kurzichalcolactone B (7) isolated from C. lucida had the lowest binding energy. It resulted in the highest total intermolecular energy from the contribution of van der Waals and hydrogen bond energy. The lowest binding energy is indicating the stable interaction of ligand and substrate. Calculation of ADMET properties resulted that some of the isolate compounds fulfilling the minimum standard parameters in ADMET properties.
Most p-coumaric acid derivatives and molecules containing phenethyl moiety have a potential in anticancer activity. Thus, combining a p-coumaroyl group and a phenethyl moiety in one compound will increase anticancer activity. The principal objective of this research was to incorporate p-coumaroyl and phenethyl moieties to form an ester, phenethyl p-coumarate (5), and an amide, N-phenethyl-p-coumaramide (6), then tested their anticancer activity using P388 leukemia murine cells. The characterization by FTIR method, compound 5 gave a strong absorption band of alkyl C-O bond that appears at 1165,00 cm-1, and compound 6 gave a sharp and medium absorption band of N-H bond that appears at 3396.64 cm-1. Docking studies of both compounds showed a hydrogen bond with Ile839 residue, and an additional hydrogen bond appeared between compound 6 and Ser991 residue. Based on their activity against P388 leukemia murine cells, these compounds are more active than their analog compounds of N-feruloylpiperidine and N-feruloylmorpholine, which have been synthesized previously. Compounds 5 and 6 have a high potential to be used as anticancer drugs.
Quantitative structure-activity relationship (QSAR) based on electronic descriptors had been conducted on 2,3-dihydro-[1,4]dioxino[2,3-f]quinazoline analogues as anticancer using DFT/B3LYP method. The best QSAR equation described as follow: Log IC50 = -11.688 + (-35.522×qC6) + (-21.055×qC10) + (-85.682×qC12) + (-32.997×qO22) + (-85.129 EHOMO) + (19.724×ELUMO). Statistical value of R2 = 0.8732, rm2 = 0.7935, r2-r02/r2 = 0.0118, PRESS = 1.5727 and Fcalc/Ftable = 2.4067 used as external validation. Atomic net charge showed as the most important descriptor to predict activity and design new molecule. Following QSAR analysis, Lipinski rules was applied to filter the design compound due to physicochemical properties and resulted that all filtered compounds did not violate the rules. Docking analysis was conducted to determine interaction between proposed compounds and EGFR protein. Critical hydrogen bond was found in Met769 residue suggesting that proposed compounds could be used to inhibit EGFR protein.
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