Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Abkürzungen
DFT
Density functional theory
DV
Degree of value
χ
Electronegativity
EGAP
Energy gap
ɳ
Hardness
HSP90AA1
Heat Shock Protein 90 Alpha family class A member 1
HOMO
Highest Occupied Molecular Orbital
LUMO
Lowest Unoccupied Molecular Orbital
MDA
Molecular docking assessment
NLR
NOD-like receptor
PPI
Protein–Protein Interaction
S
Softness
SP
SuperPred
STP
Swiss Target Prediction
Dear Editor,
Over the past few decades, Cephalotaxus alkaloids (CAs) have been considered as significant natural agents with their intriguing chemical structures and diverse bioactivities, in particular, as anti-cancer mediator. However, the investigation of its medicinal values has put in dilemma due to the limited reservoir from nature. Furthermore, the chemical synthesis of the CAs required great demanding and trial-and-error. Thus, the aim of this study was to indicate the uppermost Cephalotaxus alkaloid (CA) in chemical repository, via integrated data analysis.
Anzeige
We hypothesized the uppermost CA(s), target(s), and signaling pathway(s) can be established via cheminformatics, bioinformatics, computer screening tools, and quantum chemistry software with the holistic prospect. The CAs have potent therapeutic activities such as antileukemic, and anticancer efficacy [1]. The mainframe of structures is an azaspiranic tetracyclic scaffold (Fig. 1A). The workflow was represented in Fig. 1B.
×
First, the number of 37 CAs was piled by PubChem, and some literatures. The CAs were refined by Lipinski’s rule utilizing SwissADME platform, suggesting that the accepted 27 species are the key compounds for anti-cancer agents (Additional file 1: Table S1). Second, with accurate and rigor expanse, the intersecting targets (119) were selected between 353 and 420 targets obtained by SP and STP (Fig. 1C). The STRING database, and R Package were adopted to perform protein–protein interaction (PPI) networks (115 nodes, 603 edges), identifying certain target(s) with the highest connectivity. Consequently, heat shock protein 90 alpha family class A member 1 (HSP90AA1) with the greatest degree of value (DV; 48 degrees) was the uppermost protein coding gene to hamper cancer progression (Additional file 2: Table S2), (Fig. 1D). Notably, a report demonstrated that HSP90AA1 stabilizes the cancer cell, and overexpressed in leukemia and bladder cancer [2]. It implies that inhibition of HSP90AA1 might be a potential candidate against cancer. A bubble chart shows that the number of 37 signaling pathways associated with the 119 targets was related to the occurrence and progression of cancer (Additional file 3: Table S3). Of these, NOD-like receptor (NLR) signaling pathway indicated the smallest rich factor was defined as antagonism (Fig. 1E), indicating that the inhibitors of the signaling pathway might be promising agent(s) to treat cancer [3]. Third, an overlapping CA associated with the four targets was “Nordeoxyharringtonine”, which was also confirmed as a hub compound by molecular docking assessment (MDA), and density functional theory (DFT). The Nordeoxyharringtonine formed stable complex (< − 6.0 kcal/mol) [4] in all four targets via AutoDock 1.5.6. (Fig. 1F, G, H, I; Additional file 4: Table S4). To obtain the extensive confirmation, we performed the DFT analysis with eleven conventional anticancer drugs, indicating that the softness (S) value of the eleven anticancer drugs was between 15.77785 (eV) and 6.2278 (eV) (Fig. 1J). The softness (S) depends on EGAP (Energy gap; Highest Occupied Molecular Orbital (HOMO)—Lowest Unoccupied Molecular Orbital (LUMO) energy gap), the molecule along the lower energy gap is defined as better reactivity level. The below mathematical set was used to establish the reactivation of leading compounds.
Thus, Nordeoxyharringtonine with 10.92061(eV) was within the range (15.77785–6.2278 eV), which means that Nordeoxyharringtonine might be a promising agent to use as anticancer mediator (Table 1). Finally, we investigated the toxicity via ADMETlab2.0 and ProTox-II, identifying that Nordeoxyharringtonine had no noticeable obstacles to develop a new medication (Additional file 5: Table S5).
Table 1
The profiling of density functional theory (DFT) with eleven conventional anti-cancer drugs and Nordeoxyharringtonine
In this study, we have suggested that Nordeoxyharringtonine is the most significant CA against pan-cancer. The Nordeoxyharringtonine can be paved the way to validate anti-pan-cancer in CAs as inhibitors on multiple-targets (HSP90AA1, CASP8, TLR4, and PRKCD) to NLR signaling pathway. The key summary of this study was represented in Fig. 1K.
Anzeige
Acknowledgements
Open access publishing facilitated by Hallym University, the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology, Korea Institute for Advancement of Technology, and Bio Industrial Technology Development Program funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea).
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Fast ein Viertel der Personen mit mäßig dysplastischen Stimmlippenläsionen entwickelt einen Kehlkopftumor. Solche Personen benötigen daher eine besonders enge ärztliche Überwachung.
Bei Menschen mit Typ-2-Diabetes sind die Chancen, einen Myokardinfarkt zu überleben, in den letzten 15 Jahren deutlich gestiegen – nicht jedoch bei Betroffenen mit Typ 1.
Ob Patienten und Patientinnen mit neu diagnostiziertem Blasenkrebs ein Jahr später Bedauern über die Therapieentscheidung empfinden, wird einer Studie aus England zufolge von der Radikalität und dem Erfolg des Eingriffs beeinflusst.
„Kalte“ Tumoren werden heiß – CD28-kostimulatorische Antikörper sollen dies ermöglichen. Am besten könnten diese in Kombination mit BiTEs und Checkpointhemmern wirken. Erste klinische Studien laufen bereits.
Update Innere Medizin
Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.