Identification of TBK1 inhibitors against breast cancer using a computational approach supported by machine learning.

Introduction: The cytosolic Ser/Thr kinase TBK1 is of utmost importance in facilitating signals that facilitate tumor migration and growth. TBK1-related signaling plays important role in tumor progression, and there is need to work on new methods and workflows to identify new molecules for potential treatments for TBK1-affecting oncologies such as breast cancer. Methods: Here, we propose the machine learning assisted computational drug discovery approach to identify TBK1 inhibitors. Through our computational ML-integrated approach, we identified four novel inhibitors that could be used as new hit molecules for TBK1 inhibition. Results and Discussion: All these four molecules displayed solvent based free energy values of -48.78, -47.56, -46.78 and -45.47 Kcal/mol and glide docking score of -10.4, -9.84, -10.03, -10.06 Kcal/mol respectively. The molecules displayed highly stable RMSD plots, hydrogen bond patterns and MMPBSA score close to or higher than BX795 molecule. In future, all these compounds can be further refined or validated by in vitro as well as in vivo activity. Also, we have found two novel groups that have the potential to be utilized in a fragment-based design strategy for the discovery and development of novel inhibitors targeting TBK1. Our method for identifying small molecule inhibitors can be used to make fundamental advances in drug design methods for the TBK1 protein which will further help to reduce breast cancer incidence.

A protein-miRNA biomic analysis approach to explore neuroprotective potential of nobiletin in human neural progenitor cells (hNPCs).

Chemical-induced neurotoxicity is increasingly recognized to accelerate the development of neurodegenerative disorders (NDs), which pose an increasing health burden to society. Attempts are being made to develop drugs that can cross the blood-brain barrier and have minimal or no side effects. Nobiletin (NOB), a polymethoxylated flavonoid with anti-oxidative and anti-inflammatory effects, has been demonstrated to be a promising compound to treat a variety of NDs. Here, we investigated the potential role of NOB in sodium arsenate (NA)-induced deregulated miRNAs and target proteins in human neural progenitor cells (hNPCs). The proteomics and microRNA (miRNA) profiling was done for different groups, namely, unexposed control, NA-exposed, NA + NOB, and NOB groups. Following the correlation analysis between deregulated miRNAs and target proteins, RT-PCR analysis was used to validate the selected genes. The proteomic analysis showed that significantly deregulated proteins were associated with neurodegeneration pathways, response to oxidative stress, RNA processing, DNA repair, and apoptotic process following exposure to NA. The OpenArray analysis confirmed that NA exposure significantly altered miRNAs that regulate P53 signaling, Wnt signaling, cell death, and cell cycle pathways. The RT-PCR validation studies concur with proteomic data as marker genes associated with autophagy and apoptosis (HO-1, SQSTM1, LC-3, Cas3, Apaf1, HSP70, and SNCA1) were altered following NA exposure. It was observed that the treatment of NOB significantly restored the deregulated miRNAs and proteins to their basal levels. Hence, it may be considered one of its neuroprotective mechanisms. Together, the findings are promising to demonstrate the potential applicability of NOB as a neuroprotectant against chemical-induced neurotoxicity.

GC-MS screening of the phytochemical composition of Ziziphus honey: ADME properties and in vitro/in silico study of its antimicrobial activity.

A revival interest has been given to natural products as sources of phytocompounds to be used as alternative treatment against infectious diseases. In this context, we aimed to investigate the antimicrobial potential of Ziziphus honey (ZH) against twelve clinical bacterial strains and several yeasts and molds using in vitro and computational approaches. The well-diffusion assay revealed that ZH was able to induce growth inhibition of most Gram-positive and Gram-negative bacteria. The high mean growth inhibition zone (mGIZ) was recorded in E. coli (Clinical strain, 217), S. aureus followed by E. coli ATCC 10536 (mGIZ values: 41.00 ± 1 mm, 40.67 ± 0.57 mm, and 34.67 ± 0.57 mm, respectively). The minimal bactericidal concentrations (MBCs) and minimal fungicidal concentration values (MFCs) from approximately 266.33 mg/mL to over 532.65 mg/mL. Molecular docking results revealed that the identified compounds maltose, 2-furoic acid, isopropyl ester, 2,4-imidazolidinedione, 5-(2-methylpropyl)-(S)- and 3,4,5-trihydroxytoluene, S-Methyl-L-Cysteine, 2-Furancarboxylic acid, L-Valine-N-ethoxycarbonyl, Hexanoic acid, 3,5,5-trimethyl-, Methyl-beta-D-thiogalactoside, gamma-Sitosterol, d-Mannose, 4-O-Methylmannose, 2,4-Imidazolidinedione, 5-(2-methylpropyl)- (S) were found to have good affinity for targeted receptor, respectively. Through a 100-ns dynamic simulation research, binding interactions and stability between promising phytochemicals and the active residues of the studied enzymes were confirmed. The ADMET profiling of all identified compounds revealed that most of them could be qualified as biologically active with good absorption and permeation. Overall, the results highlighted the efficiency of ZH against the tested clinical pathogenic strains. The antimicrobial potential and the potency displayed by the identified compounds could imply their further pharmacological applications.Communicated by Ramaswamy H. Sarma.

Silver Nanoparticles Derived from Probiotic Lactobacillus casei-a Novel Approach for Combating Bacterial Infections and Cancer.

In the face of rising antibiotic resistance and the need for novel therapeutic approaches against cancer, the present study delves into the various facets of biosynthesized silver nanoparticles (AgNPs) derived from the probiotic strain Lactobacillus casei (AgNPs-LC), assessing their efficacy in combating bacterial infections, disrupting biofilm formation, interfering with quorum sensing mechanisms, and exhibiting anti-cancer properties. The results showed that the AgNPs-LC had a spherical shape with an average size of 15 nm. The biosynthesized AgNPs-LC showed a symmetrical absorption spectrum with a peak at 458 nm with a diameter of 5-20 nm. AgNPs-LC exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria and inhibited the biofilm formation (> 50% at sub-MIC) and quorum sensing-mediated virulence factors, such as the production of violacein in C. violaceum (> 80% at sub-MIC), pyocyanin in P. aeruginosa (> 70% at sub-MIC), and prodigiosin in S. marcescens (> 80% at sub-MIC). The exopolysaccharides (EPS) were also found to reduce in the presence of AgNPs-LC. Furthermore, the AgNPs-LC showed anti-cancer and anti-metastasis activity via inhibiting cell migration and invasion of human lung cancer (A-549) cells. Overall, the present study brings out the multifaceted therapeutic capabilities of AgNPs-LC which offer exciting prospects for the development of innovative biomedical and pharmaceutical interventions, making AgNPs-LC a versatile and promising candidate for a wide range of applications in healthcare and medicine. However, further research is essential to fully harness their therapeutic potential.

Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation to Elucidate the Molecular Targets and Potential Mechanism of Phoenix dactylifera (Ajwa Dates) against Candidiasis.

Candidiasis, caused by opportunistic fungal pathogens of the Candida genus, poses a significant threat to immunocompromised individuals. Natural compounds derived from medicinal plants have gained attention as potential sources of anti-fungal agents. Ajwa dates (Phoenix dactylifera L.) have been recognized for their diverse phytochemical composition and therapeutic potential. In this study, we employed a multi-faceted approach to explore the anti-candidiasis potential of Ajwa dates' phytochemicals. Utilizing network pharmacology, we constructed an interaction network to elucidate the intricate relationships between Ajwa dates phytoconstituents and the Candida-associated molecular targets of humans. Our analysis revealed key nodes in the network (STAT3, IL-2, PTPRC, STAT1, CASP1, ALB, TP53, TLR4, TNF and PPARG), suggesting the potential modulation of several crucial processes (the regulation of the response to a cytokine stimulus, regulation of the inflammatory response, positive regulation of cytokine production, cellular response to external stimulus, etc.) and fungal pathways (Th17 cell differentiation, the Toll-like receptor signaling pathway, the C-type lectin receptor signaling pathway and necroptosis). To validate these findings, molecular docking studies were conducted, revealing the binding affinities of the phytochemicals towards selected Candida protein targets of humans (ALB-rutin (-9.7 kJ/mol), STAT1-rutin (-9.2 kJ/mol), STAT3-isoquercetin (-8.7 kJ/mol), IL2-ß-carotene (-8.5 kJ/mol), CASP1-ß-carotene (-8.2 kJ/mol), TP53-isoquercetin (-8.8 kJ/mol), PPARG-luteolin (-8.3 kJ/mol), TNF-ßcarotene (-7.7 kJ/mol), TLR4-rutin (-7.4 kJ/mol) and PTPRC-rutin (-7.0 kJ/mol)). Furthermore, molecular dynamics simulations of rutin-ALB and rutin-STAT1 complex were performed to gain insights into the stability and dynamics of the identified ligand-target complexes over time. Overall, the results not only contribute to the understanding of the molecular interactions underlying the anti-fungal potential of specific phytochemicals of Ajwa dates in humans but also provide a rational basis for the development of novel therapeutic strategies against candidiasis in humans. This study underscores the significance of network pharmacology, molecular docking and dynamics simulations in accelerating the discovery of natural products as effective anti-fungal agents. However, further experimental validation of the identified compounds is warranted to translate these findings into practical therapeutic applications.

Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer's disease.

Introduction: Hyperphosphorylation of tau is an important event in Alzheimer's disease (AD) pathogenesis, leading to the generation of "neurofibrillary tangles," a histopathological hallmark associated with the onset of AD and related tauopathies. Microtubule-affinity regulating kinase 4 (MARK4) is an evolutionarily conserved Ser-Thr (S/T) kinase that phosphorylates tau and microtubule-associated proteins, thus playing a critical role in AD pathology. The uncontrolled neuronal migration is attributed to overexpressed MARK4, leading to disruption in microtubule dynamics. Inhibiting MARK4 is an attractive strategy in AD therapeutics. Methods: Molecular docking was performed to see the interactions between MARK4 and galantamine (GLT). Furthermore, 250 ns molecular dynamic studies were performed to investigate the stability and conformational dynamics of the MARK4-GLT complex. We performed fluorescence binding and isothermal titration calorimetry studies to measure the binding affinity between GLT and MARK4. Finally, an enzyme inhibition assay was performed to measure the MARK4 activity in the presence and absence of GLT. Results: We showed that GLT, an acetylcholinesterase inhibitor, binds to the active site cavity of MARK4 with an appreciable binding affinity. Molecular dynamic simulation for 250 ns demonstrated the stability and conformational dynamics of the MARK4-GLT complex. Fluorescence binding and isothermal titration calorimetry studies suggested a strong binding affinity. We further show that GLT inhibits the kinase activity of MARK4 significantly (IC50 = 5.87 µM). Conclusion: These results suggest that GLT is a potential inhibitor of MARK4 and could be a promising therapeutic target for AD. GLT's inhibition of MARK4 provides newer insights into the mechanism of GLT's action, which is already used to improve cognition in AD patients.

Exposure to pesticide residues in honey and its potential cancer risk assessment.

Honey is the most recognized natural food by-product derived from flower nectar and the upper aero-digestive tract of the honeybees. Significance of honey for its medicinal importance are well-documented in the world's oldest medical literatures. However, the current urbanization, environmental contaminations and changes in agricultural, as well as apiculture practices has led to various types of contaminations in honey. Among all, pesticide contamination has become one of the major issues worldwide. This review focuses on the recent updates concerning pesticides occurrence in honey, as well as how the repeated use and long-term exposure to honey contaminated with pesticide residues could affect the human physiological functions, possibly leading to the development of various cancers. Our findings suggests that uncontrolled use of pesticides in farming and apiculture practices leads to the occurrence of pesticides residues in honey. Therefore, regular consumption of such honey will pose a serious threat to human health, since most of the pesticides has been reported as potential carcinogens. This review will draw the attention of honey consumers, scientific communities, apiculture farmers, as well as governing bodies to strictly monitor the pesticide usage in floriculture, agriculture as well as other related practices.

Saponin-Derived Silver Nanoparticles from Phoenix dactylifera (Ajwa Dates) Exhibit Broad-Spectrum Bioactivities Combating Bacterial Infections.

The emergence of antibiotic resistance poses a serious threat to humankind, emphasizing the need for alternative antimicrobial agents. This study focuses on investigating the antibacterial, antibiofilm, and anti-quorum-sensing (anti-QS) activities of saponin-derived silver nanoparticles (AgNPs-S) obtained from Ajwa dates (Phoenix dactylifera L.). The design and synthesis of these novel nanoparticles were explored in the context of developing alternative strategies to combat bacterial infections. The Ajwa date saponin extract was used as a reducing and stabilizing agent to synthesize AgNPs-S, which was characterized using various analytical techniques, including UV-Vis spectroscopy, Fourier transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). The biosynthesized AgNPs-S exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria due to their capability to disrupt bacterial cell membranes and the leakage of nucleic acid and protein contents. The AgNPs-S effectively inhibited biofilm formation and quorum-sensing (QS) activity by interfering with QS signaling molecules, which play a pivotal role in bacterial virulence and pathogenicity. Furthermore, the AgNPs-S demonstrated significant antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals and cytotoxicity against small lung cancer cells (A549 cells). Overall, the findings of the present study provide valuable insights into the potential use of these nanoparticles as alternative therapeutic agents for the design and development of novel antibiotics. Further investigations are warranted to elucidate the possible mechanism involved and safety concerns when it is used in vivo, paving the way for future therapeutic applications in combating bacterial infections and overcoming antibiotic resistance.

Molecular Characterization of Hard Ticks Infesting Camels in the Northern Region of Saudi Arabia Using the Barcoding Gene, Mitochondrial Cytochrome oxidase subunit I.

The present study aimed to molecularly identify and characterize the hard ticks infesting camels from the northern region (Ha'il province) of Saudi Arabia using the mitochondrial barcoding gene cytochrome oxidase subunit I (COI). The sequences of tick samples from camels in three regions of Ha'il were aligned with those previously reported from different geographic regions, revealing nine haplotypes, of which six were newly described in this study for the first time. These haplotypes were used to determine their phylogenetic relationships using the maximum likelihood method, displaying two distinct clades corresponding to Hyalomma dromedarii and H. impeltatum. Moreover, the haplotypes showing the highest homology with those deposited in NCBI-GenBank from different geographic regions, including Saudi Arabia, were obtained and combined to determine their phylogenetic relationships among them. The results showed that the haplotypes belonging to two clades were grouped with those previously determined as H. dromedarii and H. impeltatum. Moreover, the presence of H. scupense (syn. H. detritum) together with H. impeltatum suggests possible asymmetrical hybridization and mitochondrial introgression between these species. H. scupense infesting different mammal species apart from camels were also clustered in a different clade, indicating the presence of different lineages of this species that show different host specificities.

Targeting NMDA receptor in Alzheimer's disease: identifying novel inhibitors using computational approaches.

The glutamate-gated ion channels known as N-methyl-d-aspartate receptors (NMDARs) are important for both normal and pathological brain function. Subunit-selective antagonists have high therapeutic promise since many pathological conditions involve NMDAR over activation, although few clinical successes have been reported. Allosteric inhibitors of GluN2B-containing receptors are among the most potential NMDAR targeting drugs. Since the discovery of ifenprodil, a variety of GluN2B-selective compounds have been discovered, each with remarkably unique structural motifs. These results expand the allosteric and pharmacolog-ical spectrum of NMDARs and provide a new structural basis for the development of next-generation GluN2B antagonists that have therapeutic potential in brain diseases. Small molecule therapeutic inhibitors targeting NMDA have recently been developed to target CNS disorders such as Alzheimer's disease. In the current study, a cheminformatics method was used to discover potential antagonists and to identify the structural requirements for Gly/NMDA antagonism. In this case we have created a useful pharmacophore model with solid statistical values. Through pharmacophore mapping, the verified model was used to filter out virtual matches from the ZINC database. Assessing receptor-ligand binding mechanisms and affinities used molecular docking. To find the best hits, the GlideScore and the interaction of molecules with important amino acids were considered essential features. We found some molecular inhibitors, namely, ZINC13729211, ZINC07430424, ZINC08614951, ZINC60927204, ZINC12447511, and ZINC18889258 with high binding affinity using computational methods. The molecules in our studies showed characteristics such as good stability, hydrogen bonding and higher binding affinities in the solvation-based assessment method than ifenprodil with acceptable ADMET profile. Moreover, these six leads have been proposed as potential new perspectives for exploring potent Gly/NMDA receptor antagonists. In addition, it can be tested in the laboratory for potential therapeutic strategies for both in vitro and in vivo research.

Biosurfactant derived from probiotic Lactobacillus acidophilus exhibits broad-spectrum antibiofilm activity and inhibits the quorum sensing-regulated virulence.

Antimicrobial resistance by pathogenic bacteria has become a global risk to human health in recent years. The most promising approach to combating antimicrobial resistance is to target virulent traits of bacteria. In the present study, a biosurfactant derived from the probiotic strain Lactobacillus acidophilus was tested against three Gram-negative bacteria to evaluate its inhibitory potential on their biofilms, and whether it affected the virulence factors controlled by quorum sensing (QS). A reduction in the virulence factors of Chromobacterium violaceum (violacein production), Serratia marcescens (prodigiosin production) and Pseudomonas aeruginosa (pyocyanin, total protease, LasB elastase and LasA protease production) was observed at different sub-MIC concentrations in a dose-dependent manner. Biofilm development was reduced by 65.76%, 70.64% and 58.12% at the highest sub-MIC levels for C. violaceum, P. aeruginosa and S. marcescens, respectively. Biofilm formation on glass surfaces exhibited significant reduction, with less bacterial aggregation and reduced formation of extracellular polymeric materials. Additionally, swimming motility and exopolysaccharides (EPS) production were shown to be reduced in the presence of the L. acidophilus-derived biosurfactant. Furthermore, molecular docking analysis performed on compounds identified through gas chromatography-mass spectrometry (GC-MS) analysis of QS and biofilm proteins yielded further insights into the mechanism underlying the anti-QS activity. Therefore, the present study has clearly demonstrated that a biosurfactant derived from L. acidophilus can significantly inhibit virulence factors of Gram-negative pathogenic bacteria. This could provide an effective method to inhibit the formation of biofilms and QS in Gram-negative bacteria.

Biosynthesized Silver Nanoparticles Derived from Probiotic Lactobacillus rhamnosus (AgNPs-LR) Targeting Biofilm Formation and Quorum Sensing-Mediated Virulence Factors.

In recent years, bacterial pathogens have developed resistance to antimicrobial agents that have created a global threat to human health and environment. As a novel approach to combating antimicrobial resistance (AMR), targeting bacteria's virulent traits that can be explained by quorum sensing (QS) is considered to be one of the most promising approaches. In the present study, biologically synthesized silver nanoparticles derived from Lactobacillus rhamnosus (AgNPs-LR) were tested against three Gram-negative bacteria to determine whether they inhibited the formation of biofilms and triggered the virulence factors controlled by QS. In C. violaceum and S. marcescens, a remarkable inhibition (>70%) of QS-mediated violacein and prodigiosin production was recorded, respectively. A dose-dependent decrease in virulence factors of P. aeruginosa (pyocyanin, pyoverdine, LasA protease, LasB elastase and rhamnolipid production) was also observed with AgNPs-LR. The biofilm development was reduced by 72.56%, 61.70%, and 64.66% at highest sub-MIC for C. violaceum, S. marcescens and P. aeruginosa, respectively. Observations on glass surfaces have shown remarkable reductions in biofilm formation, with less aggregation of bacteria and a reduced amount of extra polymeric materials being formed from the bacteria. Moreover, swimming motility and exopolysaccharides (EPS) was also found to reduce in the presence of AgNPs-LR. Therefore, these results clearly demonstrate that AgNPs-LR is highly effective in inhibiting the development of biofilms and the QS-mediated virulent traits of Gram-negative bacteria. In the future, AgNPs-LR may be used as an alternative to conventional antibiotics for the treatment of bacterial infections after careful evaluation in animal models, especially for the development of topical antimicrobial agents.

A Critical Review on Human Malaria and Schistosomiasis Vaccines: Current State, Recent Advancements, and Developments.

Malaria and schistosomiasis are two major parasitic diseases that remain leading causes of morbidity and mortality worldwide. Co-infections of these two parasites are common in the tropics, where both diseases are endemic. The clinical consequences of schistosomiasis and malaria are determined by a variety of host, parasitic, and environmental variables. Chronic schistosomiasis causes malnutrition and cognitive impairments in children, while malaria can cause fatal acute infections. There are effective drugs available to treat malaria and schistosomiasis. However, the occurrence of allelic polymorphisms and the rapid selection of parasites with genetic mutations can confer reduced susceptibility and lead to the emergence of drug resistance. Moreover, the successful elimination and complete management of these parasites are difficult due to the lack of effective vaccines against Plasmodium and Schistosoma infections. Therefore, it is important to highlight all current vaccine candidates undergoing clinical trials, such as pre-erythrocytic and erythrocytic stage malaria, as well as a next-generation RTS,S-like vaccine, the R21/Matrix-M vaccine, that conferred 77% protection against clinical malaria in a Phase 2b trial. Moreover, this review also discusses the progress and development of schistosomiasis vaccines. Furthermore, significant information is provided through this review on the effectiveness and progress of schistosomiasis vaccines currently under clinical trials, such as Sh28GST, Sm-14, and Sm-p80. Overall, this review provides insights into recent progress in malarial and schistosomiasis vaccines and their developmental approaches.

Characterization and Process Optimization for Enhanced Production of Polyhydroxybutyrate (PHB)-Based Biodegradable Polymer from Bacillus flexus Isolated from Municipal Solid Waste Landfill Site.

In recent years, there has been a growing interest in bio-based degradable plastics as an alternative to synthetic plastic. Polyhyroxybutyrate (PHB) is a macromolecule produced by bacteria as a part of their metabolism. Bacteria accumulate them as reserve materials when growing under different stress conditions. PHBs can be selected as alternatives for the production of biodegradable plastics because of their fast degradation properties when exposed to natural environmental conditions. Hence, the present study was undertaken in order to isolate the potential PHB-producing bacteria isolated from the municipal solid waste landfill site soil samples collected from the Ha'il region of Saudi Arabia to assess the production of PHB using agro-residues as a carbon source and to evaluate the growth of PHB production. In order to screen the isolates for producing PHB, a dye-based procedure was initially employed. Based on the 16S rRNA analysis of the isolates, Bacillus flexus (B. flexus) accumulated the highest amount of PHB of all the isolates. By using a UV-Vis spectrophotometer and Fourier-transform infrared spectrophotometer (FT-IR), in which a sharp absorption band at 1721.93 cm-1 (C=O stretching of ester), 1273.23 cm-1 (-CH group), multiple bands between 1000 and 1300 cm-1 (stretching of the C-O bond), 2939.53 cm-1 (-CH3 stretching), 2880.39 cm-1 (-CH2 stretching) and 3510.02 cm-1 (terminal -OH group), the extracted polymer was characterized and confirmed its structure as PHB. The highest PHB production by B. flexus was obtained after 48 h of incubation (3.9 g/L) at pH 7.0 (3.7 g/L), 35 °C (3.5 g/L) with glucose (4.1 g/L) and peptone (3.4 g/L) as carbon and nitrogen sources, respectively. As a result of the use of various cheap agricultural wastes, such as rice bran, barley bran, wheat bran, orange peel and banana peel as carbon sources, the strain was found to be capable of accumulating PHB. Using response surface methodology (RSM) for optimization of PHB synthesis using a Box-Behnken design (BBD) proved to be highly effective in increasing the polymer yield of the synthesis. With the optimum conditions obtained from RSM, PHB content can be increased by approximately 1.3-fold when compared to an unoptimized medium, resulting in a significant reduction in production costs. Thus, isolate B. flexus is a highly promising candidate for the production of industrial-size quantities of PHB from agricultural wastes and is capable of removing the environmental concerns associated with synthetic plastics from the industrial production process. Moreover, the successful production of bioplastics using a microbial culture provides a promising avenue for the large-scale production of biodegradable and renewable plastics with potential applications in various industries, including packaging, agriculture and medicine.

Computational insight into structural basis of human ELOVL1 inhibition.

Very long-chain fatty acids (VLCFAs) play a direct role in the development of a neurological disorder, X-linked adrenoleukodystrophy (X-ALD). Since ELOVL1 catalyzes the rate-limiting step of the synthesis of VLCFAs, it has emerged as an attractive target for the treatment of X-ALD. Recently two potent inhibitors, compound 22 (C22) and compound 27 (C27) have been reported to specifically inhibit human ELOVL1 but their structural basis of inhibition has not been explored. In the present study, we have used a homology model of human ELOVL1 to deduce the binding site and binding modes of C22 and C27. We have employed computational approaches to characterize the binding of C22 and C27. Initially, binding of hexacosanoyl-CoA (C26:0-CoA) to ELOVL1 was modelled and further validated by molecular dynamics (MD) simulation. We observed that the fatty acid tail of C26: CoA protrudes from a unique opening located at the occluded end of ELOVL1. Structural comparison of ELOVL1 with the crystal structure of ELOVL7 revealed that the unique opening was not present in human ELOVL7. Combined blind and focused molecular docking approaches revealed that C22 and C27 exhibit favourable binding in the same unique opening. Further, MD simulations and free binding energy calculations confirmed that C22 and C27 maintain the favourable binding in the unique opening of ELOVL1. Overall, our findings suggest that selective human ELOVL1 inhibitors block the binding of long tails of VLCFAs near the occluded end of ELOVL1. Present study will be helpful in the discovery and design of novel, selective and potent inhibitors of human ELOVL1.

Therapeutic Role of ELOVL in Neurological Diseases.

Fatty acids play an important role in controlling the energy balance of mammals. De novo lipogenesis also generates a significant amount of lipids that are endogenously produced in addition to their ingestion. Fatty acid elongation beyond 16 carbons (palmitic acid), which can lead to the production of very long chain fatty acids (VLCFA), can be caused by the rate-limiting condensation process. Seven elongases, ELOVL1-7, have been identified in mammals and each has a unique substrate specificity. Researchers have recently developed a keen interest in the elongation of very long chain fatty acids protein 1 (ELOVL1) enzyme as a potential treatment for a variety of diseases. A number of neurological disorders directly or indirectly related to ELOVL1 involve the elongation of monounsaturated (C20:1 and C22:1) and saturated (C18:0-C26:0) acyl-CoAs. VLCFAs and ELOVL1 have a direct impact on the neurological disease. Other neurological symptoms such as ichthyotic keratoderma, spasticity, and hypomyelination have also been linked to the major enzyme (ELOVL1). Recently, ELOVL1 has also been heavily used to treat a number of diseases. The current review focuses on in-depth unique insights regarding the role of ELOVL1 as a therapeutic target and associated neurological disorders.

Bacteriocin-Nanoconjugates (Bac10307-AgNPs) Biosynthesized from Lactobacillus acidophilus-Derived Bacteriocins Exhibit Enhanced and Promising Biological Activities.

The proteinaceous compounds produced by lactic acid bacteria are called bacteriocins and have a wide variety of bioactive properties. However, bacteriocin's commercial availability is limited due to short stability periods and low yields. Therefore, the objective of this study was to synthesize bacteriocin-derived silver nanoparticles (Bac10307-AgNPs) extracted from Lactobacillus acidophilus (L. acidophilus), which may have the potential to increase the bioactivity of bacteriocins and overcome the hurdles. It was found that extracted and purified Bac10307 had a broad range of stability for both temperature (20-100 °C) and pH (3-12). Further, based on Sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis, its molecular weight was estimated to be 4.2 kDa. The synthesized Bac10307-AgNPs showed a peak of surface plasmon resonance at 430 nm λmax. Fourier transform infrared (FTIR) confirmed the presence of biological moieties, and transmission electron microscopy (TEM) coupled with Energy dispersive X-Ray (EDX) confirmed that AgNPs were spherical and irregularly shaped, with a size range of 9-20 nm. As a result, the Bac10307-AgNPs displayed very strong antibacterial activity with MIC values as low as 8 µg/mL for Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa), when compared to Bac10307 alone. In addition, Bac10307-AgNPs demonstrated promising in vitro antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) (IC50 = 116.04 µg/mL) and in vitro cytotoxicity against human liver cancer cells (HepG2) (IC50 = 135.63 µg/mL), more than Bac10307 alone (IC50 = 139.82 µg/mL against DPPH and 158.20 µg/mL against HepG2). Furthermore, a protein-protein molecular docking simulation study of bacteriocins with target proteins of different biological functions was also carried out in order to ascertain the interactions between bacteriocins and target proteins.

Identifying novel and potent inhibitors of EGFR protein for the drug development against the breast cancer.

The epidermal growth factor receptor (EGFR) has been shown to be extremely important in numerous signaling pathways, particularly those involved in cancer progression. Many therapeutic inhibitors, consisting of both small molecules and monoclonal antibodies, have been developed to target inflammatory, triple-negative and metastatic breast cancer. With the emergence of resistance in breast cancer treatment strategies, there is a need to develop novel drug targets that not only overcome resistance, but also exhibit low toxicity and high specificity. The work presented here focuses on the identification of new inhibitors against the EGFR protein using combined computational approaches. Using a comprehensive machine learning-based virtual screening approach complemented by other computational approaches, we identified six new molecules from the ZINC database. The gold docking score of these six novel molecules is 125.95, 125.38, 123.13, 119.71, 115.64 and 113.73, respectively, while the gold score of the control group is 120.74. In addition, we also analyzed the FEC value of these compounds and found that the values of compounds 1, 2, 3 and 4 (-61.82, -63.98, -67.98 and -63.32, respectively) were higher are than those of the control group (-61.05). Furthermore, these molecules showed highly stable RMSD plots and good interaction of hydrogen bonds. The identified inhibitors provided interesting insights for understanding the electronic, hydrophobic, steric and structural requirements for EGFR inhibitory activity. Distinguishing these novel molecules could lead to the development of new drugs useful in treating breast cancer.Communicated by Ramaswamy H. Sarma.

Targeting inhibition of microtubule affinity regulating kinase 4 by Harmaline: Strategy to combat Alzheimer's disease.

Microtubule-affinity regulating kinase 4 (MARK4) is linked with the development of cancer, diabetes and neurodegenerative diseases. Due to its direct role in the hyperphosphorylation of tau protein, MARK4 is considered as an attractive target to fight Alzheimer's disease (AD) and neuroinflammation. In the present study, we have selected Harmaline (HAR), an alkaloid of Paganum harmala, to investigate its MARK4 inhibitory potential and its binding mechanism. Molecular docking and fluorescence binding studies were carried out to estimate the binding affinity of the HAR with the MARK4. We observed an excellent binding affinity of HAR to the MARK4 (K = 107 M-1), further complemented by isothermal titration calorimetric measurements. In addition, HAR significantly inhibits the kinase activity of MARK4 (IC50 value of 4.46 µM). Structural investigations suggested that HAR binds to the active site pocket and forms several non-covalent interactions with biologically important residues of MARK4. All-atom molecular dynamics simulation studies further advocated that the MARK4-HAR complex is stabilized throughout the trajectory of 200 ns and causes a little conformational change. All these findings suggest that HAR is a potential MARK4 inhibitor that can be implicated in managing MARK4-associated diseases, including AD.