Letters in Drug Design & Discovery - Volume 21, Issue 12, 2024

Ginger is a very renowned herbaceous plant that has been extensively used as a flavoring agent and herbal medicine for decades. It possesses a plethora of pharmacological properties, including antiinflammatory, anti-oxidant, antimicrobial, anti-diabetic, anti-tumor, anti-viral, anti-Alzheimer, analgesic, cardio-vascular, etc. In this review, a comprehensive summary of the pharmacological potentials of ginger and its bioactive components is described. Their mechanisms of action against different diseases and targets are also discussed, which can lay the foundation for their medical applications.

In the past two decades, targeted cancer therapy has emerged as a novel class of anticancer therapeutics besides traditional chemotherapy, surgery, and radiotherapy. There is an extensive variety of anticancer drugs in the market, and several compounds are in various stages of clinical trials. Many studies indicate that these cytotoxic molecules are also associated with various types of toxicity and contrary side effects; thus, researchers all over the world are working to develop more effective and safer anticancer drugs. 1,3-thiazole derivatives have recently been identified as a novel class of cancer chemotherapeutic agents with promising activity against various tumors. In this review, we have systematically summarized and highlighted the latest developments in 1,3-thiazole derivative for anticancer activity.

Supramolecular self-assembly (SA) is a naturally occurring and free energy-driven process of molecules to produce nanostructured systems depending on the assembling environment. SA molecules have captivated the research attention since they possess singular physicochemical properties that are potentially useful to make the nanostructures quite suitable for biomedical applications, such as diagnostics, drug delivery, tissue engineering, and regenerative medicine. Due to their high biological activity and low toxicity, the self-assembly properties of peptides bid certain advantages as drugs and drug delivery platforms. Among the discovered self-assembling bioactive peptides (SAPs), antimicrobial peptides (AMPs) are widely distributed through plant and animal kingdoms and play a key role as an alternative strategy to fight infections bypassing conventional antimicrobial drugs, susceptible to antimicrobial resistance. Based on this evidence, in this review, we summarized the mechanism of the self-assembling of peptides, the main forces responsible for the SAPs formation, and the studies regarding their possible implication in infectious diseases as well as wound dressing materials.

The most crucial variable that affects a drug's bioavailability is its aqueous solubility. One of the most significant issues facing the pharmaceutical business is improving water solubility, which is the key to improving therapeutic efficacy. During the first screening procedure, over 50% of recently created medications are discovered to be insoluble or weakly soluble. The solubility of the medicine can be increased using various techniques. The method entails both chemical and physical drug modifications. Any medicine that is absorbed must be present at the absorption site as a solution. Poorly soluble medications can be made more soluble using a variety of approaches, like physical and chemical alterations to the drug and other strategies. Using a surfactant, complexation, and so on are examples of solid dispersion. Pharmacological properties, absorption sites, and the requirements for the dosage form influence the choice of a solubility-improving technology. In order to serve as a quick reference, this study attempted to gather information on various solubility improvement methods and organize it systematically.

The oral route is the most common route of administration of drugs. Over 90% of all the available marketed pharmaceutical products are oral formulations. Oral drugs are used in different courses of treatment including the prevention of tooth decay. Tooth decay is the permanent damage of the enamel which leads to the formation of cavities. It can be prevented with good oral hygiene and enough fluorides in the body. Fluorides can be administered both topically (toothpastes) and systemically (supplements). Fluoride supplements fall under oral drug delivery systems. They come in the form of tablets, lozenges, and liquids. However, challenges are faced when it comes to oral drug delivery in children. The development of paediatric drugs is a difficult undertaking since many pharmaceutically active compounds have low water solubility, instability, or an unpleasant taste. Children are unable to tolerate bitter or unpleasant- tasting formulations, as well as huge pills and capsules. Due to various biological, biochemical, and physical barriers faced by oral drug delivery systems, new approaches have been developed to address these challenges such as the application of nanotechnology in drug development. Jellies for oral administration on the other hand are a new approach for the delivery of drugs with bitter tastes as well as for age groups such as children and elders. They are clear, translucent, or non-greasy semisolid products that can be used both externally and internally. In-depth, aspects of these factors will be discussed in this review paper including oral dosage forms for paediatrics, tooth decay and its pathogenesis, preventive measures and setbacks of each measure as well as the future perspectives.

Background: Prostate cancer is one of the most complex cancer and most common in elderly males. The prostate gland's malignant growth known as benign prostatic hyperplasia (BPH) is associated with lower urinary tract symptoms (LUTS) such as frequency hesitancy, and urgency. Various treatment strategies have been employed for management of prostate cancer. Due to its prolonged treatment, varying clinical treatment and high association with treatment related morbidity raise serious questions about the ideal treatment strategy for the patients. Except for skin cancer, prostate cancer is the most frequent cancer among men. Introduction: Prostate cancer cases were estimated at 14, 14,259 and 3, 75,304 persons were died globally in 2020. It is the fourth most frequent type of cancer to be discovered worldwide. It impacts over 75% of people by the time they turn 65 and its prevalence increases with age. It seems sensible that 5-alpha reductase inhibitors prevent the conversion of testosterone to dihydrotestosterone and would be used to treat benign prostatic hyperplasia because high levels of the 5-alpha reductase enzymes in humans lead to excessive levels of dihydrotestosterone in peripheral tissues. Methods: Finasteride (Proscar) and dutasteride (Avodart) are 5-alpha reductase inhibitors (5-ARIs) used in the treatment of lower urinary tract symptoms (LUTS) with prostatic enlargement as these suppress the androgens. Finasteride in clinical trials shows 25% reduction in prostate cancer in randomized trials. Dutasteride (Avodart) shows the reduction in risk of prostate cancer by 23% (approx.) but it also affect the detection of prostate cancer by affecting the levels of prostate-specific antigen. Results: The structural requirements for potential 5-alpha reductase inhibitors might be revealed via ligand-based comparative pharmacophore research employing the known strong inhibitors. These approaches can generate data can be utilized to create more effective and selective inhibitors that pharmaceutical industries can produce at a lesser price. Conclusion: 5-alpha reductase inhibitors are useful in the management of prostate cancer. However, further studies are needed to elucidate the optimal utilization, long-term effects and potential risks in prostate cancer treatment. All 5-alpha reductase inhibitor subcategories have been addressed in this review.

Inflammatory bowel disease is a chronic relapsing disorder that causes chronic inflammation and ulcers in the GIT. Depending upon the location, ulcerative colitis and Crohn's disease come under IBD. The exact etiology of IBD is still unknown. Over 8 lakhs of people were affected by inflammatory disease yearly, and the death rate increased daily. Depending upon the severity of the disease, JAK inhibitors, anti-TNF agents, and immunosuppressants can be used to manage ulcerative colitis and Crohn's disease. However, these treatments have been associated with harmful adverse effects, which cannot be ignored. To treat inflammatory diseases safely, various herbal medicines and their bioactive are preferred as game changers. Recently, the effectiveness of herbal plants has been recommended as the treatment against IBD, as shown by various in vivo models and clinical trials. The various herbal plants reported in the literature include gallic acid, lupeol, and curcumin aloe vera. This review focused on medicinal plants' anti-inflammatory, antioxidant, and anti-ulcer properties. Over 1.2 million healthcare practitioners are using herbal bioactive and have the advantages of lower side effects. Therefore, it is estimated that in Europe, the demand for plant-based products/formulations has risen by millions in 2020, showing the current position of herbal-based products in consumer health awareness.

Background: Thiosemicarbazide is an important substance in the synthesis of pharmacological and bioactive substances, and it is commonly used in the discovery of new medications. Multiple synthetic approaches exist for the creation of different thiosemicarbazide analogs, which are then discovered to treat a variety of diseases. Objective: This review paper aims to determine the growing importance of thiosemicarbazide analogs in various types of sickness by examining various unique synthetic methods that have been described to manufacture them. Methods: To incorporate published research and review papers, a comprehensive review of the literature from many sources during the past 24 years was conducted. Results: This paper summarises the findings of a literature review about the synthesis and biological activity of thiosemicarbazide and thiosemicarbazone derivatives. Conclusion: Numerous new studies on the role of thiosemicarbazide and thiosemicarbazone derivatives, as well as their methods of production and biological activity for various forms of the disease, are discussed in this review article.

1,3,4-Oxadiazole is a five-membered heterocyclic compound with one oxygen, two nitrogen, and two carbon atoms arranged in a ring. Several research reports, patents, and marketed drugs have already established 1,3,4-oxadiazole and its analog as potential molecules having a diverse range of pharmacological activities. In this review, we focused on recently acknowledged straightforward synthesis approaches for 1,3,4-oxadiazole and its analogs. Additionally, interactions of the 1,3,4-oxadiazole derivative with different biological targets (enzymes and receptors) have been described. The present findings discussed in this review analysis will aid researchers in conducting future research on 1,3,4-oxadiazole.

Background: Ubiquitin-specific protease 7 (USP7) is one of the most widely studied deubiquitin enzymes (DUBs). The protein level of USP7 is highly expressed in a variety of malignant cancers, which suggests that it is a prognostic marker of cancers and a potential drug target for oncotherapy. Objective: The aim of this study was to identify natural and effective USP7 inhibitors, in order to understand the activation of the USP7/p53 pathway by natural inhibitors. Methods: In this study, USP7 enzyme activity screening assay system and p53 luciferase reporter assay system have been applied for the discovery of natural USP7 inhibitors targeting the catalytic active site. Molecular docking and molecular dynamics (MD) simulation revealed the combined mechanism between USP7 with gardenin B. Results: The gardenin B was screened from our home-lab natural products (160 flavonoids) and had cytotoxicity in HCT116 cells (IC50 = 46.28 ± 2.16 μM). Preliminary in vitro studies disclosed its antiproliferative activity and activated p53 signaling pathway in HCT116 cells. We found that the complex formed by gardenin B and 5vsk (Ledock score = -6.86, MM/GBSA score = -53.35) had the optimal binding conformation. Moreover, the MD simulation showed that the π-π interactions between gardenin B with His461 and Phe409, and the hydrogen bonds interaction between gardenin B with Leu406 played an important role in maintaining the close binding of the complexes. Conclusion: In conclusion, gardenin B could be used as a natural product inhibitor of USP7 for further optimized design and development potential.

Background: The nuclear retinoic acid-related orphan receptor γt (RORγt) is an important transcription factor in immune cells. Functionally, RORγt plays an important role in promoting the differentiation of T helper 17 cells and regulating the expression of proinflammatory factors, such as interleukin 17. Therefore, RORγt is considered a promising target for the treatment of the autoimmune disorder. Currently, 21 RORγt inverse agonists with various scaffolds have entered clinical trials. Objective: To discover novel and potent RORγt inverse agonists, a series of novel 6-(trifluoromethyl) pyridine derivatives were designed and synthesized. Methods: We designed and synthesized a series of potent RORγt inverse agonists W1~W16 based on VTP-43742. Molecular docking, molecular dynamics (MD) simulation, and MM/GBSA were used to study the structure-activity relationship (SAR) of the derivatives. Results: The biological activity evaluation indicated that the target compounds showed potent RORγt inhibitory activity. The most active compound, W14, exhibited low nanomolar inhibitory activity (IC50 = 7.5 nM) in the luciferase reporter assay, which was superior to the clinical compound VTP-43742. Analysis of the binding mode of W14 demonstrated that the interaction of -CF3 with Leu324, Leu396, and His479 has an important contribution to the binding. Furthermore, W14 broke the H-bond formed by His479 and Tyr502 via a “push-pull” mechanism. Conclusion: Compound W14 could be used as a potential RORγt inverse agonist for further modification.

Background: Myocardial ischemia-reperfusion injury (MI/RI) is a serious complication after revascularization of myocardial infarction, which causes myocardium damage. Kukoamine A (KuA) can repress oxidative stress and neuronal apoptosis in cerebral ischemia animal models. Objective: In the present study, our objective was to explore the role of KuA in MI/RI and the underlying mechanism of KuA in oxidative stress and inflammation of MI/RI. Methods: H9c2 cells' cytotoxicity was detected using the lactate dehydrogenase (LDH) assay kit. ROS level was measured by immunofluorescence. Male C57BL/6 mice were used to establish MI/RI mice by ligating the left anterior descending coronary artery (LAD). Results: KuA treatment decreased the apoptosis and the cytotoxicity, increased the viability, and reduced the activities of myocardial infarction markers (CKMB, MYO, and cTnI) in hypoxia/ reoxygenation (H/R)-induced H9c2 cells. KuA reduced the levels of ROS, MDA, and inflammatory factors (IL-6, IL-1β, and TNF-α), and facilitated MMP and SOD levels in H/R-induced H9c2 cells. Besides, KuA activated Akt/GSK-3β axis, which was repressed by PI3K inhibitor LY294002. Moreover, KuA improved survival times, decreased the infarct size of mice, and recovered cardiac function in MI/RI mice. Finally, KuA alleviated MI/RI through Akt/GSK-3β pathway in vivo. Conclusion: Thus, KuA exerts a protective function in MI/RI through the Akt/GSK-3β axis to repress oxidative stress and inflammation.

Background: Most of the transition elements in the 3d series (first row transition metals) have been discovered to be extremely significant and practical in biological systems. Naturally, many of the enzymes that are present in the human body system act as catalysts for biological processes and are made of coordination compounds or complexes. Objective: The complex has been characterised by various spectroscopic and analytic techniques. A suitable crystal analysed by X-ray diffraction establishes the formation of a stable binuclear μ-oxo-complex with a hexacoordinate titanium centre. Methods: A new crystalline complex [Ti{La}] has been synthesised in the reaction of titanium butoxide with a phenoxyimine ligand in a 1:1 stoichiometry in toluene at room temperature under a nitrogen atmosphere. The newly synthesised Ti complex has undergone density functional theory and docking study. Results: The crystal shows a monoclinic system with space group C 1 2/c 1. X-ray crystal structure analysis reveals that this complex has a rhomboidal Ti-O-Ti core and exhibits a C2 symmetric conformation with distorted octahedral geometry. Density Functional Theory (DFT) calculations giving insights into the frontier orbitals and mulliken charge analysis, which showed good correlation with the experimental findings. Additionally, in silico molecular docking of ligand and complex was carried out against the HER2 inhibitor kinase. Conclusion: This complex exhibits a higher binding energy of ΔGb = -19.7 kcal/mol with the active pocket of HER2 (PDB:7JXH) than the ligand ΔGb = -8.5 kcal/mol.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs), which are commonly used for their anti-inflammatory and analgesic properties, have also been found to prevent cancer. (±)(R,S) Etodolac is an NSAID that belongs to the class of cyclooxygenase-2 inhibitors. Various derivatives of etodolac are synthesized to boost its anti-proliferative action and lessen its potential negative effects. In our earlier studies, some novel derivatives of etodolac exhibited stronger cytotoxic effects on prostate cell lines and had similar effects on leukemia cells in pre-screening experiments. Objective: Using the K562 leukemia cell line as a model, we sought to investigate the anti-cancer properties of a hydrazide-hydrazone derivative (SGK-205) and a 4-thiazolidinone derivative of etodolac (SGK- 216). Materials and Methods: In the current investigation, SGK-205 and SGK-216 compounds were administered to K562 cells for 24 and 48 hours at concentrations of 10, 25, 50, 75 and 100 μM. Cell viability was assessed using the MTT test, and apoptosis by Annexin V-PI staining and mitochondrial membrane potential assays, together with mRNA expressions of apoptotic proteins. The levels of the proteins, HER2 and COX2, were also examined to evaluate COX2 inhibitory capacity. Results: In K562 cells, there was a definite dose-dependent response to SGK-205 and SGK-216 compounds. Results from MTT viability tests, together with mitochondrial membrane potential measurements and Annexin V-PI staining, revealed that SGK-216 and SGK-205 significantly outperformed etodolac in terms of their apoptotic and anti-proliferative activities. The concentration range of 10-20 μM for both chemicals was sufficient to start biological responses. Apoptosis was also investigated through the expressions of pro- and anti-apoptotic proteins. Additionally, gene expression research demonstrated SGK- 205 to be a beneficial substitute to etodolac in lowering COX-2 and human epidermal growth factor receptor- 2 (HER2) expression. Conclusion: Our data indicated both derivatives to have higher anti-proliferative and apoptotic effects compared to etodolac. An overall assessment highlighting apoptotic induction potential, acceptable toxicity levels, a consistent dose-response relationship, and COX2 inhibitory actions, in particular, indicated SGK-205 as a viable novel therapeutic.

Background: Inspired by natural anti-inflammatory quaternary benzo[C]phenanthridine alkaloids, novel 2-phenylphthalazin-2-ium bromides were previously designed and synthesized. Objective: The anti-inflammatory effect of 2-phenylphthalazin-2-ium bromides was evaluated based on inflammatory cytokines, and their possible mechanism was explored through the NF-ΚB, TLR4 and MAPK signaling pathways. Methods: The tested concentrations of two compounds were assessed using MTT assay in vitro. Griess assay was used to determine the changes in nitric oxide (NO) in the cell culture supernatant. qRT128;’PCR was used to detect the mRNA levels of inflammatory cytokines, such as IL-6, IL-1ß, IL-10, TNF-α, TLR4 and iNOS. The secretion levels of TNF-α and IL-1β were detected by ELISA. Western blot test was used to detect the protein expression of IL-6, IL-10, TLR4, iNOS, NF-ΚB, p-P38/P38, p- ERK/ERK and p-JNK/JNK. Results: 2-(3,5-Dichlorophenyl)phthalazin-2-ium bromide (2) with a concentration below 1 μg/mL showed no significant effect on the growth inhibition of RAW264.7 cells, so the concentrations of compound 2 used for experiments were set to 0, 0.25, 0.5 and 1 μg/mL. Compared with the blank control group, the model group showed increased release of NO, transcription levels of IL-6, IL-1ß, IL-10, TNF-α, TLR4 and iNOS (p<0.05), and ratios of p-P38/P38, p-ERK/ERK, p-JNK/JNK (p<0.05). Compared with the model group, the sample groups displayed decreased NO release and reduced transcriptional levels of IL-6, IL-1ß, IL-10, TNF-α, TLR4, and iNOS and reduced protein expression ratios of IL-6, IL-1ß, IL-10, TNF-α, NF-ΚB, TLR4, iNOS, p-P38/P38, p-ERK/ERK and p- JNK/JNK (p<0.05). Conclusion: This study showed that 2-phenylphthalazin-2-ium bromides partially protected macrophages from the LPS-induced inflammatory response by suppressing TLR4-NF-ΚB/MAPK signaling and reducing NO production.

Introduction: The chemotherapy medication cisplatin is highly effective and is used in treating a wide variety of cancers. Tumor resistance and dose-related severe side effects, including kidney and hearing damage and suppressed bone marrow function, limit its clinical utility. This study aimed to investigate the nephroprotective effect of alpha-pinene against cisplatin-induced nephrotoxicity in male albino Wistar rats. Methods: A total of 24 rats were divided into four groups containing six animals. Alpha-pinene (50 mg/kg) was administered orally for 14 days, and cisplatin (50 mg/kg) was given intraperitoneally for the last two consecutive days (13th and 14th day). Kidney function markers, lipid peroxidative markers, antioxidant status, inflammatory markers, and apoptotic gene expressions were analyzed. The cisplatininduced rats significantly elevated kidney function markers, inflammatory markers, and pro-apoptotic genes in kidney tissues. Further, the antioxidant level/activities and antiapoptotic gene expression were significantly diminished in cisplatin-induced rats. Results: Pretreatment with alpha-pinene significantly decreased kidney function markers, inflammatory markers, and pro-apoptotic genes and increased antioxidant status and antiapoptotic genes. Conclusion: These findings provide the protective effect of alpha-pinene against CP-induced nephrotoxicity, as measured by potent antioxidant and antiapoptotic properties.

Background: Amoebiasis is caused by Entamoeba histolytica, a pathogenic species living on human colon tissues. Metronidazole is currently used for the treatment of amoebiasis, but resistance of E. histolytica to the use of such treatment has been reported. Therefore, the development of new antiamoebic drugs is still very much needed for clinical treatment. Preliminary research on extract and fractions from Cratoxylum sumatranum stem bark has shown their anti-amoebic activity. Two compounds from the cage xanthone groups, cochinchinoxanthone and cochinchinone D, have been isolated from the active fraction of C. sumatranum stem bark. Objective: This study aimed to investigate the anti-amoebic activity of the two known compounds against E. histolytica. Methods: The in silico method used was molecular docking with several receptors, including thioredoxin reductase, triose phosphate isomerase, pyruvate ferredoxin oxidoreductase, Giardia fructose-1,6- bisphosphate aldolase, serine acetyltransferase, and phosphoserine phosphatase. The prediction of ADMET properties was also carried out for both the compounds. Results: The results showed cochinchinone D to have a higher binding affinity to thioredoxin reductase, pyruvate ferredoxin oxidoreductase, and Giardia fructose-1,6-bisphosphate aldolase receptors than cochinchinoxanthone. In contrast, cochinchinoxanthone bound better to the triose phosphate isomerase and phosphoserine phosphatase receptors, while both exhibited the same affinity for serine acetyltransferase. In general, the two compounds were also found to have similar ADMET profiles. Conclusion: In conclusion, caged xanthone compounds from C. sumatranum have the potential to be developed as anti-amoebic agents against E. histolytica through the mechanism of inhibition of these enzymes.

Aim: Major depression and anxiety have increased significantly worldwide since the 2019 outbreak of COVID-19. The development of highly effective antidepressants with low side effects is attracting researchers. Methods: Monoamine oxidase A (MAO-A) is a key enzyme that catalyzes the metabolism of norepinephrine (NE), dopamine (DA), and serotonin (5-HT), etc. Elevated level of MAO-A would lead to increased metabolism of its substrates, thereby causing a decrease in the levels of these neurotransmitter monoamines in the brain leading to depression. Consequently, inhibition of MAO-A was thought to be an effective strategy, as this would treat the root cause of depression. Results and Discussion: Based on the crystal structure of MAO-A, 4 star-hits, as potential MAO-A inhibitors was screened from the compound libraries with central nervous system (CNS) activity by using various computational techniques. Molecular dynamics simulation was used to verify the stability of the ligand- receptor complexes. Conclusion: Furthermore, the ADMET (absorption, distribution, metabolism, excretion and toxicity properties) of the virtual hits were predicted in order to evaluate their lead-like properties and safety. This work provides ideas for the drugs discovery of antidepressant.

Background: Parkinson's disease (PD) is a chronic neurodegenerative disease affecting mostly aged people. The disease's symptoms develop gradually over time and include tremors, bradykinesia, rigidity, and postural instability. Current treatment options for PD are only symptom-targeted. Prolyl oligopeptidase (POP) is a serine protease enzymes implicated in PD pathogenesis via an increase in the aggregation of α-synuclein protein in the brain. Aim: This study aims to identify potent anti-PD ligands with inhibitory potential against POP. Methods: Ligand-based pharmacophore modeling, Glide extra precision (XP) docking, and postsimulation analysis methods were used. Results: The adopted ligand-based (LB) modeling generated pharmacophoric features, including 1 hydrophobic group, 1 positive ionizable group, 2 aromatic rings, and 2 hydrogen bond acceptors. A total of 23 hits with a Gunner-Henry score of 0.7 and an enrichment factor of 30.24 were obtained as validation protocols, making it an ideal model. The LB model retrieved 177 hit compounds from the 69,543 natural screening ligands available in the Interbioscreen database. Interestingly, ligands 1, 2, 3, 4, and 5 orderly demonstrated higher binding affinities with Glide XP docking of -9.0, -8.8, -8.7, -8.7, -8.7 kcal/mol compared to reference drugs, GSK552 and ZPP with -8.2, and -6.8 kcal/mol respectively. Similarly, their MM/GBSA values were recorded as -54.4, -51.3, -58.4, -49.3, - 33.5, & -32.5 kJ/mol respectively. Further, MD analysis indicated that ligands had higher favorable binding and stability to the receptor. Conclusion: Overall, the study paves the way for developing potential anti-PD therapeutics. The ligands are recommended as adjuvant/single candidate as anti-PD candidates upon further experiment.

Background: Breast cancer accounts for 30% of all new female cancers yearly. Bioinformatics serves us to find new biomarkers and facilitate future experimental research. Exploring a distinct network of competing endogenous RNA (ceRNA) that includes potential prognostic, diagnostic, and therapeutic biomarkers is captivating. Methods: Differentially expressed lncRNAs, mRNAs, and miRNAs were collected using Gene Expression Omnibus datasets. DEGs were validated based on TCGA. Functional analysis and pathway activity were also done. Drug sensitivity analyses were done, and IC50 vs. gene expression plots were depicted. Results: A total of 696 mRNAs, 48 lncRNAs, and, 43 miRNAs were identified to have significant differential expression in cancerous breast tissue than normal breast tissue samples. Functional analysis showed significant pathway enrichments in cancer. We found that 13 individual genes, lncRNAs, and miRNAs, CDC6, ERBB2, EZR, HELLS, MAPK13, MCM2, MMP1, SLC7A5, TINCR, TRIP13, hsa-miR-376a, hsa-miR-21, hsa-miR-454 were significantly predictive of poor overall survival and AKAP12, CXCL12, FGF2, IRS2, LINC00342, LINC01140, MEG3, MIR250HG, NAV3, NDRG2, NEAT1, TGFBR3 and, hsa-miR-29c were associated with favorable overall survival. We reached a set of five genes (EGR1, NFIB, TGFBR3, SMARCA4, and MCM2) that exhibit altered expression patterns in breast cancer, resulting in increased susceptibility of cancer cells to certain drug treatments. Conclusion: We successfully made a unique ce-network, providing new clues to understand the regulatory functions of non-coding RNAs (miRNAs and lncRNAs) in the pathogenesis and prognosis of breast cancer and will facilitate further experimental studies to develop new biomarkers in the diagnosis, prognosis and, therapy of breast cancer.