In our previous work, the partitions (1 mg/mL) of Ageratum conyzoides (AC) aerial parts and Ixora coccinea (IC) leaves showed inhibitions of 94% and 96%, respectively, whereas their fractions showed IC50 43 and 116 µg/mL, respectively, toward Matrix Metalloproteinase9 (MMP9), an enzyme that catalyzes a proteolysis of extracellular matrix. In this present study, we performed IC50 determinations for AC n-hexane, IC n-hexane, and IC ethylacetate partitions, followed by the cytotoxicity study of individual partitions against MDA-MB-231, 4T1, T47D, MCF7, and Vero cell lines. Successive fractionations from AC n-hexane and IC ethylacetate partitions led to the isolation of two compounds, oxytetracycline (OTC) and dioctyl phthalate (DOP). The result showed that AC n-hexane, IC n-hexane, and IC ethylacetate partitions inhibit MMP9 with their respective IC50 as follows: 246.1 µg/mL, 5.66 µg/mL, and 2.75 × 10−2 µg/mL. Toward MDA-MB-231, 4T1, T47D, and MCF7, AC n-hexane demonstrated IC50 2.05, 265, 109.70, and 2.11 µg/mL, respectively, whereas IC ethylacetate showed IC50 1.92, 57.5, 371.5, and 2.01 µg/mL, respectively. The inhibitions toward MMP9 by OTC were indicated by its IC50 18.69 µM, whereas DOP was inactive. A molecular docking study suggested that OTC prefers to bind to PEX9 rather than its catalytic domain. Against 4T1, OTC showed inhibition with IC50 414.20 µM. In conclusion, this study furtherly supports the previous finding that AC and IC are two herbals with potential to be developed as triple-negative anti-breast cancer agents.
Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme for the homeostasis and metabolism of intracellular folate. However, it is known that one of the commonly found MTHFR gene SNPs (A222V) causes a decrease in activity which decreases folate levels and increases the accumulation of homocysteine in the blood. The purpose of this study was to investigate the molecular dynamics of MTHFR wild-type protein and MTHFR A222V mutant protein in silico. After some preparations, the crystal structure of MTHFR with code 6FCX obtained from the Protein Data Bank was used as the input file for molecular dynamics (MD) simulations. YASARA-Structure was employed for performing 50 ns production run of MD simulations. The deviation of the root-mean-squared deviation value of the backbone atoms (∆RMSDBb) of MTHFR wild-type is consistently less than 2 Å from the beginning of the MD simulations production runs. On the other hand, there is a sudden spike of ∆RMSDBb of MTHFR A222V from 15.01 to 20.00 ns of 2.221 Å. According to the analysis of ∆RMSDBb, MTHFR wild-type protein is considered stable and the MTHFR A222V mutant protein is considered unstable which may lead to various clinical problems for the person possessing this mutation.
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