Comprehensive computational target fishing approach to identify Xanthorrhizol putative targets

Abstract

Xanthorrhizol (XNT), is a bioactive compound found in Curcuma xanthorrhiza Roxb. This study aimed to determine the potential targets of the XNT via computational target fishing method. This compound obeyed Lipinski’s and Veber’s rules where it has a molecular weight (MW) of 218.37 gmol-1, TPSA of 20.23, rotatable bonds (RBN) of 4, hydrogen acceptor and donor ability is 1 respectively. Besides, it also has half-life (HL) values 3.5 h, drug-likeness (DL) value of 0.07, oral bioavailability (OB) of 32.10, and blood–brain barrier permeability (BBB) value of 1.64 indicating its potential as therapeutic drug. Further, 20 potential targets were screened out through PharmMapper and DRAR-CPI servers. Co-expression results derived from GeneMANIA revealed that these targets made connection with a total of 40 genes and have 744 different links. Four genes which were RXRA, RBP4, HSD11B1 and AKR1C1 showed remarkable co-expression and predominantly involved in steroid metabolic process. Furthermore, among these 20 genes, 13 highly expressed genes associated with xenobiotics by cytochrome P450, chemical carcinogenesis and steroid metabolic pathways were identified through gene ontology (GO) and KEGG pathway analysis. In conclusion, XNT is targeting multiple proteins and pathways which may be exploited to shape a network that exerts systematic pharmacological effects.

Anti-breast cancer synthetic peptides derived from the Anabas testudineus skin mucus fractions

“…Zhou et al also confirmed that the HPEPDOCK could significantly predict the native global and local protein-peptide docking compared to other servers 42 , 57 . This finding is in agreement with the previous studies stated that the antimicrobial peptide could inhibit the cancer cell line, such as Jurkat cells SCC-4 cell and MCF7, by modulating the expression of tumour suppressor gene p53 leading to activation of pro-apoptotic gene Bax and inhibiting the anti-apoptotic gene BCL2 56 , 58 – 61 . The result of proteins immunoprecipitation of the current study proves the validity of the findings of the proteins predictions analysis; which confirmed that AtMP1 and AtMP2 interact with tumour suppressor gene p53 and modulate the apoptosis-related proteins (caspase-3, 7, 8, 9, p53, BCL2, and Bax), leading to induction of apoptosis and arrest the growth of breast cancer cell lines in G0/1 phase.…”

“…The result of proteins immunoprecipitation and the LC–MS analysis proves the validity of the findings of the proteins-peptides interaction prediction and RT 2 PCR analysis, which confirmed that AtMP1 and AtMP2 interact with tumour suppressor gene p53 and modulate the apoptosis-related proteins (caspase-9, caspase-3, caspase-7, caspase-8, p53, BCL2, and Bax), leading to induction of apoptosis and arrest the growth of breast cancer cell lines in G0/1 phase. These results were consistent with the findings reported by 42 , 55 , 56 , which found that novel web servers, such as ZDOCK and HPEPDOCK, were useful for specific blind peptide-protein docking. Zhou et al also confirmed that the HPEPDOCK could significantly predict the native global and local protein-peptide docking compared to other servers 42 , 57 .…”

In Vitro Replication Inhibitory Activity of Xanthorrhizol against Severe Acute Respiratory Syndrome Coronavirus 2

“…Both SCoV2 and SCoV1 are known to be sensitive to type I IFNs, although the IFN-mediated canonical and noncanonical antiviral responses can be blunted by these CoVs [ 61 ]. A recent study predicted 20 potential molecular targets of XNT using a computational target fishing approach [ 62 ]. Some of the predicted host targets of XNT appear to be linked to antiviral responses triggered by type I IFN.…”

“…No signs of toxicity were observed in mice following the oral administration of 2000 mg/kg body weight of C. xanthorrhiza extract [ 66 ] or a single compound XNT at a concentration of 500 mg/kg [ 67 ]. ADME (absorption, distribution, metabolism, excretion)-related properties of XNT support the drug-likeness of XNT [ 62 ]. With its safety profile in pre-clinical trials in mice [ 15 , 67 , 68 ], clinical testing of its antiviral efficacy against SCoV2 and HCoV is warranted.…”

Recent Advances in In Silico Target Fishing

“…The tool automatically finds the best poses for the query molecule screened against all the pharmacophoric models present in the protein databases, such as TTD and PDTD [94], and selects the best hits. PharmMapper has been used for identifying a wide variety of targets including those of capsaicin [122], salvianolic acid [123], and xanthorrhizol [124]. Moreover, this tool has resulted to be efficient in identifying the polypharmacological profile of drugs [30], allowing finding of more than one target for the same molecule, and contributing to the previously mentioned drug repurposing.…”