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Background: Hepatitis C virus (HCV) is an enveloped and positive-stranded RNA virus that is a major causative agent of chronic liver diseases worldwide. HCV has become the main cause of liver transplantations and there is no effective drug for all hepatitis genotypes. Elucidation of life cycle and nonstructural proteins of HCV involved in viral replication are the attractive targets for the development of antiviral drugs. Methods: In this work, pharmacoinformatics approaches coupled with docking analyses were applied on HCV nonstructural proteins to identify the novel potential hits and HCV drugs. Molecular docking analyses were carried out on HCV approved drugs followed by the ligand-based pharmacophore generation to screen the antiviral libraries for novel potential hits. Results: Virtual screening technique has made known the top-ranked five novel compounds (ZINC00607900, ZINC03635748, ZINC03875543, ZINC04097464, and ZINC12503102) along with the least binding energy (-8.0 kcal/mol, -6.1 kcal/mol, -7.5 kcal/mol, -7.4 kcal/mol, and -7.3 kcal/mol respectively) and stability with non-structural proteins target. Conclusion: These promising hits exhibited better absorption and ADMET properties as compared to the selected drug molecules. These potential compounds extracted from in silico approach may be significant in drug design and development against Hepatitis and other liver diseases.

Nanotechnology is now playing an emerging role in green synthesis in agriculture as nanoparticles (NPs) are used for various applications in plant growth and development. Copper is a plant micronutrient; the amount of copper oxide nanoparticles (CuONPs) in the soil determines whether it has positive or adverse effects. CuONPs can be used to grow corn and wheat plants by combining Bacillus subtilis. In this research, CuONPs were synthesized by precipitation method using different precursors such as sodium hydroxide (0.1 M) and copper nitrate (Cu(NO

Background: Escherichia coli various strains can cause alarmingly serious infections. Countries like Pakistan harbour the class of bacteria with one of the highest rates of resistance, but very little has been done to explore their genetic pool. Objectives: This study was designed to find out the frequency of virulence genes of Uropathogenic E. coli and their association with antibiotic resistance along with the evolutionary adaptation of the selected gene through the phylogenetic tree. Methods: Isolates from 120 urinary tract infected patients were collected. Antibiotic sensitivity was detected by the disk diffusion method and DNA extraction was done by the boiling lysis method followed by PCR-based detection of virulence genes. The final results were analysed using the chi-square test. Results: The isolates were found to be least susceptible to nalidixic acid, followed by ampicillin, cotrimoxazole, cefotaxime, ciprofloxacin, aztreonam, amoxicillin, gentamycin, nitrofurantoin and imipenem. The iucC was the most common virulence gene among the resistant isolates. About 86% of the collected samples were found to be multi-drug resistant. Statistical analysis revealed a significant association between the iucC gene and resistance to ampicillin (P=0.03) and amoxicillin (P=0.04), and also between fimH and resistance to aztreonam (P=0.03). Conclusion: This study unravels the uncharted virulence genes of UPEC in our community for the very first time. We report a high frequency of the iucC and fimH virulence genes. This, along with their positive association with resistance to beta-lactam antibiotics in the studied community, indicates their important role in the development of complicated UTIs.

Background: Cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) is an imperative enzyme due to its immersion in the biotransformation of a wide range of drugs and other xenobiotics. The involvement of enzymes in drug metabolism indicates an effective drug target for the development of novel therapeutics. The discovery of CYP1A1 specific inhibitors would be of particular relevance for the clinical pharmacology. Method: In the current work, in silico approaches were utilized to identify the novel potential compounds through a diverse set of reported inhibitors against CYP1A1. A dataset of reported compounds against CYP1 belongs to 10 different classes (alkaloids, coumarins, flavonoids, natural compounds, synthetic inhibitors, drugs, MBI’s, PAHs, naphthoquinone and stilbenoids) was retrieved and utilized for the comparative molecular docking analyses followed by pharmacophore modeling. The total eleven novel compounds were scrutinized on the basis of the highest binding affinities and least binding energy values. Result: ZINC08792486 compound attained the highest gold fitness score of 90.11 against CYP1A1 among all the scrutinized molecules. Conclusion: It has been elucidated that the residues Phe-224, Gly-316 and Ala-317 were conserved in all ligand-receptor interactions and critical for the development of effective therapies. The ADMET property analyses also predict better absorption and distribution of the selected hits that may be used in the future for in vitro validations and drug development.

Owing to the dominant functions of mitochondria in multiple cellular metabolisms and distinct types of regulated cell death, maintaining a functional mitochondrial network is fundamental for the cellular homeostasis and body fitness in response to physiological adaptations and stressed conditions. The process of mitophagy, in which the dysfunctional or superfluous mitochondria are selectively engulfed by autophagosome and subsequently degraded in lysosome, has been well formulated as one of the major mechanisms for mitochondrial quality control. To date, the PINK1-PRKN-dependent and receptors (including proteins and lipids)-dependent pathways have been characterized to determine the mitophagy in mammalian cells. The mitophagy is highly responsive to the dynamics of endogenous metabolites, including iron-, calcium-, glycolysis-TCA-, NAD(+)-, amino acids-, fatty acids-, and cAMP-associated metabolites. Herein, we summarize the recent advances toward the molecular details of mitophagy regulation in mammalian cells. We also highlight the key regulations of mammalian mitophagy by endogenous metabolites, shed new light on the bidirectional interplay between mitophagy and cellular metabolisms, with attempting to provide a perspective insight into the nutritional intervention of metabolic disorders with mitophagy deficit. Abbreviations: acetyl-CoA: acetyl-coenzyme A; ACO1: aconitase 1; ADCYs: adenylate cyclases; AMPK: AMP-activated protein kinase; ATM: ATM serine/threonine kinase; BCL2L1: BCL2 like 1; BCL2L13: BCL2 like 13; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; Ca(2+): calcium ion; CALCOCO2: calcium binding and coiled-coil domain 2; CANX: calnexin; CO: carbon monoxide; CYCS: cytochrome c, somatic; DFP: deferiprone; DNM1L: dynamin 1 like; ER: endoplasmic reticulum; FKBP8: FKBP prolyl isomerase 8; FOXO3: forkhead box O3; FTMT: ferritin mitochondrial; FUNDC1: FUN14 domain containing 1; GABA: γ-aminobutyric acid; GSH: glutathione; HIF1A: hypoxia inducible factor 1 subunit alpha; IMMT: inner membrane mitochondrial protein; IRP1: iron regulatory protein 1; ISC: iron-sulfur cluster; ITPR2: inositol 1,4,5-trisphosphate type 2 receptor; KMO: kynurenine 3-monooxygenase; LIR: LC3 interacting region; MAM: mitochondria-associated membrane; MAP1LC3: microtubule associated protein 1 light chain 3; MFNs: mitofusins; mitophagy: mitochondrial autophagy; mPTP: mitochondrial permeability transition pore; MTOR: mechanistic target of rapamycin kinase; NAD(+): nicotinamide adenine dinucleotide; NAM: nicotinamide; NMN: nicotinamide mononucleotide; NO: nitric oxide; NPA: Niemann-Pick type A; NR: nicotinamide riboside; NR4A1: nuclear receptor subfamily 4 group A member 1; NRF1: nuclear respiratory factor 1; OPA1: OPA1 mitochondrial dynamin like GTPase; OPTN: optineurin; PARL: presenilin associated rhomboid like; PARPs: poly(ADP-ribose) polymerases; PC: phosphatidylcholine; PHB2: prohibitin 2; PINK1: PTEN induced kinase 1; PPARG: peroxisome proliferator activated receptor gamma; PPARGC1A: PPARG coactivator 1 alpha; PRKA: protein kinase AMP-activated; PRKDC: protein kinase, DNA-activated, catalytic subunit; PRKN: parkin RBR E3 ubiquitin protein ligase; RHOT: ras homolog family member T; ROS: reactive oxygen species; SIRTs: sirtuins; STK11: serine/threonine kinase 11; TCA: tricarboxylic acid; TP53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VDAC1: voltage dependent anion channel 1

Introduction:Pseudomonas aeruginosa is one of the major pathogens associated with the acute tissue damage in patients having Diabetic Foot Ulcer (DFU). The treatment of such infections can be an uphill battle due to the serious resistance to all the mainstay antibiotics, owing to overzealous production of Extended-Spectrum Beta-Lactamases (ESBLs). Pakistan also has a high prevalence of diabetes and complications related to it, however genetic disposition of the pathogens remains underinvestigated.Aim:The main objective of the study was to determine the frequency of ESBLs in Multi-drug resistant P. aeruginosa from diabetic foot patients.Methods:The duration of the present study was one year and 100 patients having DFU were enrolled. All the pus samples were subjected to the bacterial culture, gram staining, catalase test, oxidase test and antimicrobial susceptibility pattern to various antibiotics for the confirmation of P. aeruginosa. Of 23 positive isolates of P. aeruginosa, 10 were ESBLs positive as detected by double disk diffusion test. The positive ESBL strain shows an increase of ≥5mm in the zone of inhibition of the combination discs in comparison to the alone ceftazidime disc.Results:The ESBLs positive strains were also tested for TEM-1, SHV-1, PER-1, and VEB-1, where: (07/10) strains carried SHV-1, (05/10) strains were positive for TEM-1, while none of the isolates were PCR-positive for PER-1 and VEB-1.Conclusion:The findings of the current study show a difference in the pattern of ESBL genes compared to that of other such endeavors. The present study also warrants the PCR-based detection of the type of ESBL as a potential factor to consider in deciding the therapeutic strategy at any point during the treatment.

Schizophrenia (SZ) is a complex disabling disorder that leads to the mental disability and afflicts 1% of the world's total population and placed in top ten medical disorders. In current work, bioinformatics analyses were carried out on Trace amine (TA)-associated receptor 6 (TAAR6) to recognize the potential drugs and compounds against SZ. Comparative modeling and threading-based approaches were utilized for the structure prediction of TAAR6. Fifty-nine predicted structures were evaluated by various model assessment techniques and final model having only eight amino acids in the outlier region and 98.5% overall quality factor was chosen for further pharmacoinformatics and molecular docking analyses. From an extensive literature review, 11 Food and Drug Administration (FDA) approved drugs were analyzed by computational techniques and Aripiprazole was found as the most effective drug against SZ by targeting TAAR6. Here, we report five novel molecules which exhibited the highest binding affinity, effective drug properties, and interestingly, observed better results than the approved selected drugs against SZ by targeting TAAR6. The docking analyses revealed that Arg-92, Trp-98, Gln-191, Thr-192, Ala-290, Cys-291, Tyr-293, and Glu-294 residues were observed as critical interacting residues in receptor-ligand interactions. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, Lipinski rule of five, highest binding affinity coupled with virtual screening (VS), and pharmacophore modeling approach illustrated that aripiprazole (-8.6 kcal/mol) and TAAR6_0094 (-9.3 kcal/mol) are potential inhibitors for targeting TAAR6. It is suggested that schizophrenic patients have to use Aripiprazole for the medication of SZ by targeting TAAR6 and develop effective therapies by utilizing scrutinized novel compound.

Background: Leishmaniasis, which is classified by the World Health Organization (WHO) as one of the Neglected Tropical Diseases (NTDs) faces several challenges in terms of successful chemotherapy and novel drug developments. Objective: The aim of the present study was to develop a Self-Emulsifying Drug Delivery System (SEDDS) for the hydrophobic polyphenol pigment curcumin to enable it for its potential use in cutaneous and mucocutaneous leishmaniasis. Methods: Two Curcumin-loaded formulations SNEDD-A and B, were developed. Both were characterized by the droplet size, PDI and zeta potential and evaluated for the cytotoxicity on Caco-2 cell lines and through hemolysis test on red blood cells. The spreading potential of the formulations was checked over buccal mucosa and damaged skin model. Antileishmanial activities were performed against promastigote, axenic amastigote and macrophage harbored amastigotes of Leishmania tropica parasite. Results: SNEDDS-A and B had minor differences in physical characteristics. In the toxicological assay, the viability of the Caco-2 cells was 87.5 % for SNEDDS-A and 88.9% for SNEDDS-B while both caused 1-2% hemolysis. Both had remarkable spreading potential, covering 8cm2 of buccal mucosa and damaged the skin for less than 45 minutes. The Antileishmanial activities of the SNEDDS-A in terms of IC50 were 0.13 µg/ml and 0.25 µg/ml against promastigote and amastigote, respectively while IC50 values of SNEDDS-B were 0.18 µg/ml and 0.27 µg/ml against promastigote and amastigote, respectively. Both the formulations killed 100% of the macrophage harbored Leishmania tropica parasites at a concentration of 4.4 µg/ml. Conclusion: Our results demonstrate that both the SEDDS formulations of curcumin have the potential to provide a promising tool for curcumin for its use through topical routes in the treatment of cutaneous and mucocutaneous leishmaniasis.

Background. Coronaviruses (CoVs) are enveloped positive-strand RNA viruses which have club-like spikes at the surface with a unique replication process. Coronaviruses are categorized as major pathogenic viruses causing a variety of diseases in birds and mammals including humans (lethal respiratory dysfunctions). Nowadays, a new strain of coronaviruses is identified and named as SARS-CoV-2. Multiple cases of SARS-CoV-2 attacks are being reported all over the world. SARS-CoV-2 showed high death rate; however, no specific treatment is available against SARS-CoV-2. Methods. In the current study, immunoinformatics approaches were employed to predict the antigenic epitopes against SARS-CoV-2 for the development of the coronavirus vaccine. Cytotoxic T-lymphocyte and B-cell epitopes were predicted for SARS-CoV-2 coronavirus protein. Multiple sequence alignment of three genomes (SARS-CoV, MERS-CoV, and SARS-CoV-2) was used to conserved binding domain analysis. Results. The docking complexes of 4 CTL epitopes with antigenic sites were analyzed followed by binding affinity and binding interaction analyses of top-ranked predicted peptides with MHC-I HLA molecule. The molecular docking (Food and Drug Regulatory Authority library) was performed, and four compounds exhibiting least binding energy were identified. The designed epitopes lead to the molecular docking against MHC-I, and interactional analyses of the selected docked complexes were investigated. In conclusion, four CTL epitopes (GTDLEGNFY, TVNVLAWLY, GSVGFNIDY, and QTFSVLACY) and four FDA-scrutinized compounds exhibited potential targets as peptide vaccines and potential biomolecules against deadly SARS-CoV-2, respectively. A multiepitope vaccine was also designed from different epitopes of coronavirus proteins joined by linkers and led by an adjuvant. Conclusion. Our investigations predicted epitopes and the reported molecules that may have the potential to inhibit the SARS-CoV-2 virus. These findings can be a step towards the development of a peptide-based vaccine or natural compound drug target against SARS-CoV-2.

Both iron metabolism and mitophagy, a selective mitochondrial degradation process via autolysosomal pathway, are fundamental for the cellular well-being. Mitochondria are the major site for iron metabolism, especially the biogenesis of iron-sulfur clusters (ISCs) via the mitochondria-localized ISCs assembly machinery. Here we report that mitochondrial ISCs biogenesis is coupled with receptor-mediated mitophagy in mammalian cells. Perturbation of mitochondrial ISCs biogenesis, either by depleting iron with the iron chelator or by knocking down the core components of the mitochondrial ISCs assembly machinery, triggers FUNDC1-dependent mitophagy. IRP1, one of the cellular iron sensors to maintain iron homeostasis, is crucial for iron stresses induced mitophagy. Knockdown of IRP1 disturbed iron stresses induced mitophagy. Furthermore, IRP1 could bind to a newly characterized IRE in the 5’ untranslated region of the Bcl-xL mRNA and suppress its translation. Bcl-xL is an intrinsic inhibitory protein of the mitochondrial phosphatase PGAM5, which catalyzes the dephosphorylation of FUNDC1 for mitophagy activation. Alterations of the IRP1/Bcl-xL axis navigate iron stresses induced mitophagy. We conclude that ISCs serve as physiological signals for mitophagy activation, thus coupling mitophagy with iron metabolism., Graphical abstract Image 1, Highlights • Perturbation of ISCs biogenesis triggers FUNDC1 dependent mitophagy. • IRP1 targets a newly characterized IRE in Bcl-xL mRNA to suppress its translation. • IRP1/Bcl-xL axis navigates iron stresses induced mitophagy and dominates mitochondrial redox response.

Aging is an unavoidable process, leading to cell senescence due to physiochemical changes in an organism. Anti-aging remedies have always been of great interest since ancient times. The purpose of anti-aging activities is to increase the life span and the quality of life. Anti-aging activities are primarily involved in the therapies of age-related disorders such as Parkinson's Disease (PD), Alzheimer's Disease (AD), cardiovascular diseases, cancer, and chronic obstructive pulmonary diseases. These diseases are triggered by multiple factors that are involved in numerous molecular pathways including telomere shortening, NF-κB pathway, adiponectin receptor pathway, insulin, and IGF signaling pathway, AMPK, mTOR, and mitochondria dysfunction. Natural products are known as effective molecules to delay the aging process through influencing metabolic pathways and thus ensure an extended lifespan. These natural compounds are being utilized in drug design and development through computational and high throughput techniques for effective pro-longevity drugs. A comprehensive study on natural compounds demonstrating their anti-aging activities along with databases of natural products for drug designing was executed and summarized in this review article.

Pest management in stored grain industry is a global issue due to the development of insecticide resistance in stored grain insect pests. Excessive use of insecticides at higher doses poses a serious threat of food contamination and residual toxicity for grain consumers. Since the development of new pesticide incurs heavy costs, identifying an effective synergist can provide a ready and economical tool for controlling resistant pest populations. Therefore, the synergistic property of quercetin with paraoxon and tetraethyl pyrophosphate has been evaluated against the larvae and adults of Tribolium castaneum (Herbst). Comparative molecular docking analyses were carried out to further identify the possible mechanism of synergism. It was observed that quercetin has no insecticidal when applied at the rate of 1.5 and 3.0 mg/g; however, a considerable synergism was observed when applied in combination with paraoxon. The comparative molecular docking analyses of CYP450 monooxygenase (CYP15A1, CYP6BR1, CYP6BK2, CYP6BK3) family were performed with quercetin, paraoxon and tetraethyl pyrophosphate which revealed considerable molecular interactions, predicting the inhibition of CYP450 isoenzyme by all three ligands. The study concludes that quercetin may be an effective synergist for organophosphate pesticides depending upon the dose and type of the compound. In addition, in silico analyses of the structurally diversified organophosphates can effectively differentiate the organophosphates which are synergistic with quercetin.

Hypertension is considered as one of the most common diseases that affect human beings (both male and female) due to its high prevalence and also extending widely to both industrialize and developing countries. Angiotensin-converting enzyme (ACE) has a significant role in the regulation of blood pressure and ACE inhibition with inhibitory peptides is considered as a major target to prevent hypertension. In the current study, a blood pressure regulating honey protein (MRJP1) was examined to identify the ACE inhibitory peptides. The 3D structure of MRJP1 was predicted by utilizing the threading approach and further optimized by performing molecular dynamics simulation for 30 nanoseconds (ns) to improve the quality factor up to 92.43%. Root mean square deviation and root mean square fluctuations were calculated to evaluate the structural features and observed the fluctuations in the timescale of 30 ns. AHTpin server based on scoring vector machine of regression models, proteolysis and structural characterization approaches were implemented to identify the potential inhibitory peptides. The anti-hypertensive peptides were scrutinized based on the QSAR models of anti-hypertensive activity and the molecular docking analyses were performed to explore the binding affinities and potential interacting residues. The peptide "EALPHVPIFDR" showed the strong binding affinity and higher anti-hypertensive activity along with the global energy of -58.29 and docking score of 9590. The aromatic amino acids especially Tyr was observed as the key residue to design the dietary peptides and drugs like ACE inhibitors.

Background: Synapsin II regulates neurotransmitter release from mature nerve terminals and plays important role in the formation of new nerve terminals. The associations of SYN II are identified in various studies that are linked to the onset of Schizophrenia. Schizophrenia is characterized by abnormal behavior like obsession, dampening of emotions and auditory hallucination. Methods: The bioinformatics approaches were utilized for structural modeling and docking analyses of SYN II followed by pharmacophore generation to identify potent inhibitors. Results: The comparative modeling approach was employed to generate the 3D model having 82.404% quality factor calculated by Errat. Pharmacophore was constructed by utilizing merge molecular and chemical features of selected five FDA approved Schizophrenia drugs by LigandScout 4.1.5. Comparative docking analyses were performed by utilizing the selected drugs and top screened hits by GOLD and AutoDock Vina. Conclusion: It was proposed that Aripiprazole drug and scrutinized compounds have strong binding affinities among the other selected drugs. The reported compounds may be used for further analyses in the drug discovery processes, as they have shown good human intestinal absorption and are noncarcinogenic. The present study provides the structural insights which may be used for further understating of the Schizophrenia therapeutic purposes by targeting SYN II and other inhibitors haunting.

Mitophagy is an essential process for mitochondrial quality control and turnover. It is activated by two distinct pathways, one dependent on ubiquitin and the other dependent on receptors including FUNDC1. It is not clear whether these pathways coordinate to mediate mitophagy in response to stresses, or how mitophagy receptors sense stress signals to activate mitophagy. We find that the mitochondrial E3 ligase MARCH5, but not Parkin, plays a role in regulating hypoxia‐induced mitophagy by ubiquitylating and degrading FUNDC1. MARCH5 directly interacts with FUNDC1 to mediate its ubiquitylation at lysine 119 for subsequent degradation. Degradation of FUNDC1 by MARCH5 expression desensitizes mitochondria to hypoxia‐induced mitophagy, whereas knockdown of endogenous MARCH5 significantly inhibits FUNDC1 degradation and enhances mitochondrial sensitivity toward mitophagy‐inducing stresses. Our findings reveal a feedback regulatory mechanism to control the protein levels of a mitochondrial receptor to fine‐tune mitochondrial quality.

Studies on Schizophrenia so far reveal a complex picture of neurological malfunctioning reported to be strongly associated with DAOA. Detailed sequence analyses proved DAOA as a primate specific gene having conserved gene desert region on both upstream and downstream region. The analyses of 10 MB chromosomal region of primates, birds, rodents, and reptiles having DAOA evidenced the conserved part in primates and in the rest of species, whileDAOAis only present in primates. DAOA has four isoforms having one interaction partner DAO. Protein-protein analyses of four DAOA isoforms with DAO were performed individually and find potential interacting residues computationally. It was observed that molecular docking of approved FDA drugs revealed efficient results but there was no common drug with effective binding to all DAOA isoforms. Library of compounds was constructed by virtual screening of 2D similarity search against recommended SZ drugs in conjunction with their physiochemical properties. Molecular docking resulted in six novel compounds exhibiting maximum binding affinity with selected four DAOA isoforms. However not the entire schizophrenic population responds to the single drug and interestingly in this study six novel compounds having promising results and same binding site to that DAOA that may be used to interact with DAO against four DAOA isoforms were observed.

Studies on Schizophrenia, so far reveal a complex picture of neurological malfunctioning reported to be strongly associated with proline dehydrogenase (PRODH). This study employs in silico hybrid approach for virtual screening and molecular docking followed by pharmacophore identification and structural modeling. Docking studies revealed critical residues for receptor-ligand interaction. Virtual screening approach coupled with docking energies and drug likeness rules, suggested that of 8 compounds, Clozapine, MCULE-1620364835-0 (Drug Score 88 %) and PB-752728400 (Drug Score 85 % and Binding energy 8.1 kcal/mol) observed as potential inhibitor compounds for targeting PRODH. Energy score of selected compounds were better than the previous listed drug analogs. ALDH4A1, functional partner of PRODH showed strong interactions with PRODH.

The aim of current effort is too sentient that the people should have to know what is happening and to explore the reasons behind the veil of reasons so they can generate and amend their opinions and deduce their own conclusions. The most worthy asset of a researcher is to publish valuable research and must first be earned the scientific professional integrity and then maintained it. The scientific community must obey the scientific ethical norms and rules if they want to play its due role. Still, we are bearing ethical quandaries in our research and we have to solve them for advancement of research in scientific community including Pakistan.

RASSF2, potential tumor suppressor gene, acts as a KRAS-specific effectors protein and may promote apoptosis and cell cycle arrest. It stabilizes STK3/MST2 by protecting it from proteasomal degradation. RASSF2 plays a significant role against the inhibition of cancer. MODELLER (9v15) and online servers (I-Tasser, SwissModel, 3D-JigSaw, ModWeb) were utilized to generate 3D structures of the RASSF2 based on homology modeling. A comparison between models predicted by MODELLER (9v15) and Web servers had been checked through utilized evaluation tools. The most potent model for RASSF2 was analyzed and selected for molecular docking studies. The binding pockets were revealed for binding studies through Site Hound. AutoDock Vina and AutoDock4 were utilized for molecular docking, and the attempt of this experiment was to identify the ligands for RASSF2. The selected compounds may act as regulators and regulate the normal activity of RASSF2. It was also analyzed and observed that the selected compounds showed least binding energy and high-affinity binding in predicted top binding domain. The determination of protein function is based on accurate identification of binding sites in protein structures. The binding site is known, and it may allow the ligand type and protein function to be determined by performing in silico and experimental procedures. The detection, comparison, and analysis of binding pockets are pivotal to drug discovery. It proposed that predicted structure is reliable for the structural insights and functional studies. The predicted binding pockets may lead to further analysis (drug discovery), used against cancer study.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia, excessive acetylcholinesterase (AChE) activity, formation of neurotoxic amyloid plaque, and tau protein aggregation. Based on literature survey, we have shortlisted three important target proteins (AChE, COX2, and MMP8) implicated in the pathogenesis of AD and 20 different phytocompounds for molecular docking experiments with these three target proteins. The 3D-structures of AChE, COX2, and MMP8 were predicted by homology modeling by MODELLER and the threading approach by using ITASSER. Structure evaluations were performed using ERRAT, Verify3D, and Rampage softwares. The results based on molecular docking studies confirmed that there were strong interactions of these phytocompounds with AChE, COX2, and MMP8. The top three compounds namely Albiziasaponin-A, Iso-Orientin, and Salvadorin showed least binding energy and highest binding affinity among all the scrutinized compounds. Post-docking analyses showed the following free energy change for Albiziasaponin-A, Salvadorin, and Iso-Orientin (−9.8 to −15.0 kcal/mol) as compared to FDA approved drugs (donepezil, galantamine, and rivastigmine) for AD (−6.6 to −8.2 Kcal/mol) and interact with similar amino acid residues (Pro-266, Asp-344, Trp-563, Pro-568, Tyr-103, Tyr-155, Trp-317, and Tyr-372) with the target proteins. Furthermore, we have investigated the antioxidant and anticholinesterase activity of these top three phytochemicals namely, Albiziasaponin-A, Iso-Orientin, and Salvadorin in colchicine induced rat model of AD. Sprague Dawley (SD) rat model of AD were developed using bilateral intracerebroventricular (ICV) injection of colchicine (15 μg/rat). After the induction of AD, the rats were subjected to treatment with phytochemicals individually or in combination for 3 weeks. The serum samples were further analyzed for biomarkers such as 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), matrix metalloproteinase-8 (MMP-8), isoprostanes-2 alpha (isoP-2α), and acetylcholine esterase (AChE) using conventional Enzyme Linked Immunosorbent Assay (ELISA) method. Additionally, the status of lipid peroxidation was estimated calorimetrically by measuring thiobarbituric acid reactive substances (TBARS). Here, we observed a statistically significant reduction (P < 0.05) in the oxidative stress and inflammatory markers in the treatment groups receiving mono and combinational therapies using Albiziasaponin-A, Iso-Orientin, and Salvadorin as compared to colchicine alone group. Besides, the ADMET profiles of these phytocompounds were very promising and, hence, these potential neuroprotective agents may further be taken for preclinical studies either as mono or combinational therapy for AD.

Dengue, still a "Neglected Tropical Disease" is somehow injustice and remains uncontrolled globally. World Health Organization (2012-2020) reported that the world's half population is living in dengue-affected regions. Therefore, effective drug candidates or promising vaccines are urgently needed to control the dengue. It is an acute febrile disease caused by mosquito borne dengue viruses (DENVs) which belong to the genus Flavivirus with four serotypes. In present work, immunoinformatics approach was utilized to predict the antigenic epitopes of dengue proteins for the development of DENV vaccine. B-cell and cytotoxic T-lymphocyte epitopes were predicted for NS3 dengue protein. Docking complexes of 17 antigenic B-cell epitopes of various lengths and 4 CTL epitopes with antigenic sites were investigated followed by binding interaction analyses of top predicted peptides with MHC-I HLA-A2 molecule. These predicted epitopes with antigenic amino acids might present a preliminary set of peptides for future vaccine development against DENV.

STING (stimulator of interferon genes) is a central molecule that binds to cyclic dinucleotides produced by the cyclic GMP-AMP synthase (cGAS) to activate innate immunity against microbial infection. Here we report that STING harbors classic LC-3 interacting regions (LIRs) and mediates autophagy through its direct interaction with LC3. We observed that poly(dA:dT), cGAMP, and HSV-1 induced STING-dependent autophagy and degradation of STING immediately after TBK1 activation. STING induces non-canonical autophagy that is dependent on ATG5, whereas other autophagy regulators such as Beclin1, Atg9a, ULK1, and p62 are dispensable. LIR mutants of STING abolished its interaction with LC3 and its activation of autophagy. Also, mutants that abolish STING dimerization and cGAMP-binding diminished the STING-LC3 interaction and subsequent autophagy, suggesting that STING activation is indispensable for autophagy induction. Our results thus uncover dual functions of STING in activating the immune response and autophagy, and suggest that STING is involved in ensuring a measured innate immune response.

Schizophrenia (SZ) is a severe manifesting psychiatric neural disorder with abnormal behavior, disorganized speech and figment of the imagination. The Synapsin II (SYN2) and Trace Amine Associated Receptor (TAAR6) genes has direct association with SZ. In the current study, the 3-dimensional structure of SYN2 and TAAR6 protein is proposed and the protein-protein docking analysis was applied to explore the binding interactions of the candidate proteins. The comparative modeling was performed with the suitable template (Q86VA8 for SYN2 and H0YF79 for TAAR6) which represents the query coverage (71%, 87%), sequence identity (67%, 34%) and the e-value (0.0, 1e-43) respectively. The structure quality of the predicted model of SYN2 and TAAR6 presents 90.7%, and 96.5% residues in the favored region of Ramachandran plot analysis respectively, suggests the good quality models construction. The phylogenetic analysis suggests that the TAAR6 sequence is conserved in chimpanzee and gorilla (>80% homology) whereas the SYN2 is closely related with macaque. The protein docking analysis of SYN2 shows five ionic interactions with Lys-256, Lys-539, Arg-475, Gln-536 and Gln-529 with His-121, Glu-467, Glu-472, Arg-458 and Asp-477 of CAPON. The TAAR6 have two interactions of Glu-33 and Gly-171 with Arg-85 and Lys-52 of the PPP3CC. Current computational study may play a significant role to recruit, analyze and cure the mysteries of schizophrenia neurodegenerative disorder.

Migraine, a complex debilitating neurological disorder is strongly associated with potassium channel subfamily K member 18 (KCNK18). Research has emphasized that high levels of KCNK18 may be responsible for improper functioning of neurotransmitters, resulting in neurological disorders like migraine. In the present study, a hybrid approach of molecular docking and virtual screening were followed by pharmacophore identification and structure modeling. Screening was performed using a two-dimensional similarity search against recommended migraine drugs, keeping in view the physicochemical properties of drugs. LigandScout tool was used for exploring pharmacophore properties and designing novel molecules. Here, we report the screening of four novel compounds that have showed maximum binding affinity against KCNK18, obtained through the ZINC database, and Drug and Drug-Like libraries. Docking studies revealed that Asp-46, Ile-324, Ile-44, Gly-118, Leu-338, Val-113, and Phe-41 are critical residues for receptor–ligand interaction. A virtual screening approach coupled with docking energies and druglikeness rules illustrated that ergotamine and PB-414901692 are potential inhibitor compounds for targeting KCNK18. We propose that selected compounds may be more potent than the previously listed drug analogs based on the binding energy values. Further analysis of these inhibitors through site-directed mutagenesis could be helpful for exploring the details of ligand-binding pockets. Overall, the findings of this study may be helpful for designing novel therapeutic targets to cure migraine., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: http://dvpr.es/QTrQxw

From last decade, there has been progressive improvement in computational drug designing. Several diseases are being cured from different plant extracts and products. Rheumatoid Arthritis (RA) is the most shared disease among auto-inflammatory diseases. Tumour necrosis factor (TNF)-α is associated with RA pathway and has adverse effects. Extensive literature review showed that plant species under study (Cannabis sativa, Prunella vulgaris and Withania somnifera) possess anti-inflammatory, anti-arthritic and anti-rheumatic properties. 13 anti-inflammatory compounds were characterised and filtered out from medicinal plant species and analysed for RA by targeting TNF-α through in silico analyses. By using ligand based pharmacophore generation approach and virtual screening against natural products libraries we retrieved twenty unique molecules that displayed utmost binding affinity, least binding energies and effective drug properties. The docking analyses revealed that Ala-22, Glu-23, Ser-65, Gln-67, Tyr-141, Leu-142, Asp-143, Phe-144 and Ala-145 were critical interacting residues for receptor-ligand interactions. It is proposed that the RA patients should use reported compounds for the prescription of RA by targeting TNF-α. This report is opening new dimensions for designing innovative therapeutic targets to cure RA.