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Background: Amyloid β (Aβ) fibril agglomeration is crucial in Alzheimer’s disease (AD) etiology, leading to significant harm to the central nervous system. Polyphenols have been investigated for their capacity to hinder Aβ agglomeration. Objective: This investigation aimed to assess the potential of Ajwa date palm (Phoenix dactylifera)-based bioactives in binding and disrupting resilient Aβ1-42 fibrils through in-silico studies. Methods: The primary phytochemicals present in date palms were subjected to molecular docking with three different conformers of Aβ1-42 and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis. The stability of the system was assessed through molecular dynamics (MD) simulation. Results: It was noted that Diosmetin, Rutin, and Genistein effectively bind with 2BEG, 2MXU, and 2NAO fibrils, respectively, with docking energies ranging from −7.2 to −8.2 kcal/mol. Diosmetin, Rutin, and Genistein show notable pharmacokinetic variability, with LogP values from −1.69–2.58, with 1–6 rotatable bonds, and total polar surface areas (TPSA) between 112.52 and 240.90 Å2, characteristics important for drug candidacy evaluation. Their ADMET properties include solubility values of −3.238 to −3.595 mol/L, intestinal absorption of 23.4–93.4%, and VDss ranging from 0.094 to 1.663 L/kg. The ensuing MS simulations spanning 100 ns, illuminated the establishment of a robust peptide-chemical complex. Hydrophobic interactions, ionic and hydrogen bonds play a critical role in the ligand binding with their respective targets. Conclusions: These findings underscore the potential of these botanicals as leads for developing potent Aβ agglomeration inhibitors. However, before introducing into clinical settings, these findings need to be validated further.

Arsenic (As), an environmental pollutant, imposes toxic impacts on plant health. In recent years, researchers have focused on comprehending the As-induced intrusion in growth and metabolic components. However, the interactions between phosphorus (P) and silicon (Si) remain elusive, specifically in rice (Oryza sativa) cultivars. Therefore, the present study investigated the effects of P and Si on the defense mechanisms, nutrients accumulation, carbohydrate metabolism, gibberellic acid (GA3) synthesis, and growth responses in Indica rice cultivars (landrace and improved) under As stress. With this focus, our study potentially indicated that As stress (150 µM) negatively impacted the underlying physiological and growth traits, with more pronounced effects on the improved cultivar compared to the landrace. However, P (30 mg kg−1 soil) and/ or Si (1 mM) treatments have prominently reduced oxidative stress with improved defense mechanisms and GA synthesis. Modulation of enzymatic defense system increased in both cultivars but more pronounced in landrace, including superoxide dismutase (+36.47%, +24.43%), ascorbate peroxidase (+95.11%, +78.26%), along with non-enzymatic antioxidants such as ascorbate (+29.43%, +21.48%), and reduced glutathione (+75.45%, +62.34%) concentrations, respectively. Notably, GA concentration (+23.78%, +16.48%) was substantially increased by the cumulative application of P and Si under As stress in both cultivars but more conspicuous in the landrace, respectively. Further, employing GA biosynthesis inhibitor, paclobutrazol (PBZ; 10 µM), substantiated the input of GA-mediated As tolerance, wherein, PBZ reversed the impacts of P and Si on the endogenous GA concentration and defense metabolism. In summation, landrace outperformed improved cultivar leading to As tolerance. This implies that the landrace could be used for future breeding programs permitting in-depth considerations of P and Si-mediated GA3 synthesis under As stress conditions.

Abstract This study focused on developing novel pyridine-3-carboxamide analogs to treat bacterial wilt in tomatoes caused by Ralstonia solanacearum. The analogs were synthesized through a multistep process and their structures confirmed using spectroscopy. Molecular docking studies identified the most potent analog from the series. A specific analog, compound 4a, was found to significantly enhance disease resistance in tomato plants infected with R. solanacearum. The structure–activity relationship analysis showed the positions and types of substituents on the aromatic rings of compounds 4a–i strongly influenced their biological activity. Compound 4a, with a chloro group at the para position on ring C and hydroxyl group at the ortho position on ring A, was exceptionally effective against R. solanacearum. When used to treat seeds, the analogs displayed remarkable efficacy, especially compound 4a which had specific activity against bacterial wilt pathogens. Compound 4a also promoted vegetative and reproductive growth of tomato plants, increasing seed germination and seedling vigor. In plants mechanically infected with bacteria, compound 4a substantially reduced the percentage of infection, pathogen quantity in young tissue, and disease progression. The analogs were highly potent due to their amide linkage. Molecular docking identified the best compounds with strong binding affinities. Overall, the strategic design and synthesis of these pyridine-3-carboxamide analogs offers an effective approach to targeting and controlling R. solanacearum and bacterial wilt in tomatoes.

The escalation of many coronavirus variants accompanied by the lack of an effective cure has motivated the hunt for effective antiviral medicines. In this regard, 18 Saudi Arabian medicinal plants were evaluated for SARS CoV-2 main protease (Mpro) inhibition activity. Among them, Terminalia brownii and Acacia asak alcoholic extracts exhibited significant Mpro inhibition, with inhibition rates of 95.3 % and 95.2 %, respectively, at a concentration of 100 µg/mL. Bioassay-guided phytochemical study for the most active n-butanol fraction of T. brownii led to identification of eleven compounds, including two phenolic acids (1, and 2), seven hydrolysable tannins (3–10), and one flavonoid (11) as well as four flavonoids from A. asak (12–15). The structures of the isolated compounds were established using various spectroscopic techniques and comparison with known compounds. To investigate the chemical interactions between the identified compounds and the target Mpro protein, molecular docking was performed using AutoDock 4.2. The findings identified compounds 4, 5, 10, and 14 as the most potential inhibitors of Mpro with binding energies of −9.3, −8.5, −8.1, and −7.8 kcal mol−1, respectively. In order to assess the stability of the protein–ligand complexes, molecular dynamics simulations were conducted for a duration of 100 ns, and various parameters such as RMSD, RMSF, Rg, and SASA were evaluated. All selected compounds 4, 5, 10, and 14 showed considerable Mpro inhibiting activity in vitro, with compound 4 being the most powerful with an IC50 value of 1.2 µg/mL. MM-GBSA free energy calculations also revealed compound 4 as the most powerful Mpro inhibitor. None of the compounds (4, 5, 10, and 14) display any significant cytotoxic activity against A549 and HUVEC cell lines.

Antibiotics have revolutionized medicine, saving countless lives since their discovery in the early 20th century. However, the origin of antibiotics is now overshadowed by the alarming rise in antibiotic resistance. This global crisis stems from the relentless adaptability of microorganisms, driven by misuse and overuse of antibiotics. This article explores the origin of antibiotics and the subsequent emergence of antibiotic resistance. It delves into the mechanisms employed by bacteria to develop resistance, highlighting the dire consequences of drug resistance, including compromised patient care, increased mortality rates, and escalating healthcare costs. The article elucidates the latest strategies against drug-resistant microorganisms, encompassing innovative approaches such as phage therapy, CRISPR-Cas9 technology, and the exploration of natural compounds. Moreover, it examines the profound impact of antibiotic resistance on drug development, rendering the pursuit of new antibiotics economically challenging. The limitations and challenges in developing novel antibiotics are discussed, along with hurdles in the regulatory process that hinder progress in this critical field. Proposals for modifying the regulatory process to facilitate antibiotic development are presented. The withdrawal of major pharmaceutical firms from antibiotic research is examined, along with potential strategies to re-engage their interest. The article also outlines initiatives to overcome economic challenges and incentivize antibiotic development, emphasizing international collaborations and partnerships. Finally, the article sheds light on government-led initiatives against antibiotic resistance, with a specific focus on the Middle East. It discusses the proactive measures taken by governments in the region, such as Saudi Arabia and the United Arab Emirates, to combat this global threat. In the face of antibiotic resistance, a multifaceted approach is imperative. This article provides valuable insights into the complex landscape of antibiotic development, regulatory challenges, and collaborative efforts required to ensure a future where antibiotics remain effective tools in safeguarding public health.

This study was undertaken to investigate the interaction between the sodium channel blocker amiloride (AML) and human serum albumin (HSA). A combination of multi-spectroscopic techniques and computational methods were employed to identify the AML binding site on HSA and the forces responsible for the formation of the HSA–AML complex. Our findings revealed that AML specifically binds to Sudlow’s site II, located in subdomain IIIA of HSA, and that the complex formed is stabilized using van der Waals hydrogen-bonding and hydrophobic interactions. FRET analysis showed that the distance between AML and Trp214 was optimal for efficient quenching. UV-Vis spectroscopy and circular dichroism indicated minor changes in the structure of HSA after AML binding, and molecular dynamics simulations (MDS) conducted over 100 ns provided additional evidence of stable HSA–AML-complex formation. This study enhances understanding of the interaction between AML and HSA and the mechanism responsible.

Introduction The emergence of a new and highly pathogenic coronavirus (SARS-CoV-2) in Wuhan (China) and its spread worldwide has resulted in enormous social and economic losses. Amongst many proteins encoded by the SARS-CoV-2 genome, the main protease (Mpro) or chymotrypsin-like cysteine protease (3CLpro) and papain-like protease (PLpro) serve as attractive drug targets. Material and methods We screened a library of 2267 natural compounds against Mpro and PLpro using high throughput virtual screening (HTVS). Fifty top-scoring compounds against each protein in HTVS were further evaluated by standard-precision (SP) docking. Compounds with SP docking energy of ≤ –8.0 kcal/mol against Mpro and ≤ –5.0 kcal/mol against PLpro were subjected to extra-precision (XP) docking. Finally, six compounds against each target proteins were identified and subjected to Prime/MM-GBSA free energy calculations. Compounds with the lowest Prime/MM-GBSA energy were subjected to molecular dynamics simulation to evaluate the stability of protein-ligand complexes. Results Proanthocyanidin and rhapontin were identified as the most potent inhibitors of Mpro and PLpro, respectively. Analysis of protein-inhibitor interaction revealed that both protein-inhibitor complexes were stabilized by hydrogen bonding and hydrophobic interactions. Proanthocyanidin interacted with the catalytic residues (His41 and Cys145) of Mpro, while rhapontin contacted the active site residues (Trp106, His272, Asp286) of PLpro. The docking energies of proanthocyanidin and rhapontin towards their respective targets were –10.566 and –10.022 kcal/mol. Conclusions This study’s outcome may support application of proanthocyanidin and rhapontin as a scaffold to build more potent inhibitors with desirable drug-like properties. However, it requires further validation by in vitro and in vivo studies.

Tartrazine (Tz) is a yellow food color dye that is used in a range of foods to make them more appealing and attractive. However, very limited information is there about its interaction with macromolecules, like different proteins that are components of the food products. In this work the bovine beta-lactoglobulin (BLG) aggregation stimulating properties of Tz have been studied at pH 2.0. Spectroscopic, microscopic and molecular docking have been used to characterize the aggregation inducing property of Tz in BLG protein at pH 2.0. The spectroscopic techniques i.e., turbidity and RLS measurements showed that the 0.1–10.0 mM of Tz induces aggregation in BLG at pH 2.0. The aggregates were found to have well defined amyloid-like morphology as observed by CD and TEM. The amyloid fibrils were found long, straight and unbranched. Molecular docking results ascertained that Tz binds at the hydrophobic cavity and interact with the key amino acid residues involved in the interaction with different ligands. The spectroscopic, microscopic and computational results support that the electrostatic, as well as hydrophobic interactions, played a very important role in Tz-induced BLG fibrillation. Keywords: Tartrazine, Beta-lactoglobulin, Food additive dye, Amyloid fibril, pH

Salicylic acid (SA) is a well-known plant growth regulator, which participates in many physiological processes of plants under normal and stressful conditions. In this study, we investigated the impact of SA supplementation on the components of ascorbate-glutathione cycle and glyoxalase system, photosynthesis and growth of rice (Oryza sativa) plants subjected to arsenic (As) stress. Plants grown with As exhibited enhanced As uptake, increased oxidative stress, and photosynthesis and growth inhibition. Application of SA promoted photosynthesis and growth in plants with or without As stress by improving plant defense systems and reducing oxidative stress through interaction with ethylene and nitric oxide (NO). SA acted as an ethylene antagonist, reducing stress ethylene formation under As stress, while NO formation was induced. This resulted in coordinated control over the antioxidant defense systems and enhanced As tolerance, protecting photosynthesis and growth from As-induced damage. The study showed that positive responses of SA in promoting photosynthesis and growth under As stress were the result of its interplay with ethylene and NO, enhanced capacity of defense systems to reduce oxidative stress. The crosstalk of SA with ethylene and NO will be useful in augmenting the performance of rice plants under As stress.

Alzheimer’s disease (AD) is a progressive neurological disorder that affects 50 million people. Despite this, only two classes of medication have been approved by the FDA. Therefore, we have planned to develop therapeutics by multitarget approach. We have explored the library of 2029 natural product-like compounds for their multi-targeting potential against AD by inhibiting AChE, BChE (cholinergic pathway) MAO-A, and MOA-B (oxidative stress pathway) through in silico high-throughput screening and molecular dynamics simulation. Based on the binding energy of these target enzymes, approximately 189 compounds exhibited a score of less than −10 kcal/mol against all targets. However, none of the control inhibitors exhibited a binding affinity of less than −10 kcal/mol. Among these, the top 10 hits of compounds against all four targets were selected for ADME-T analysis. As a result, only F0850-4777 exhibited an acceptable range of physicochemical properties, drug-likeness, pharmacokinetics, and suitability for BBB permeation with high GI-A and non-toxic effects. The molecular dynamics study confirmed that F0850-4777 remained inside the binding cavity of targets in a stable conformation throughout the simulation and Prime-MM/GBSA study revealed that van der Waals’ energy (ΔGvdW) and non-polar solvation or lipophilic energy (ΔGSol_Lipo) contribute favorably towards the formation of a stable protein–ligand complex. Thus, F0850-4777 could be a potential candidate against multiple targets of two pathophysiological pathways of AD and opens the doors for further confirmation through in vitro and in vivo systems.

The present study was aimed to evaluate the suitability of agro-wastes and crude vegetable oils for the cost-effective production of poly-β-hydroxybutyrate (PHB), to evaluate growth kinetics and PHB production in Alcaligenes faecalis RZS4 and Pseudomonas sp. RZS1 with these carbon substrates and to study the biodegradation of PHB accumulated by these cultures. Alcaligenes faecalis RZS4 and Pseudomonas sp. RZS1 accumulates higher amounts of PHB corn (79.90% of dry cell mass) and rice straw (66.22% of dry cell mass) medium respectively. The kinetic model suggests that the Pseudomonas sp. RZS1 follows the Monod model more closely than A. faecalis RZS4. Both the cultures degrade their PHB extract under the influence of PHB depolymerase. Corn waste and rice straw appear as the best and cost-effective substrates for the sustainable production of PHB from Alcaligenes faecalis RZS4 and Pseudomonas sp. RZS1. The biopolymer accumulated by these organisms is biodegradable in nature. The agro-wastes and crude vegetable oils are good and low-cost sources of nutrients for the growth and production of PHB and other metabolites. Their use would lower the production cost of PHB and the low-cost production will reduce the sailing price of PHB-based products. This would promote the large-scale commercialization and popularization of PHB as an ecofriendly bioplastic/biopolymer.

The effects of nitric oxide (NO) as 100 µM sodium nitroprusside (SNP, NO donor) on photosynthetic-nitrogen use efficiency (NUE), photosynthetic-sulfur use efficiency (SUE), photosynthesis, growth and agronomic traits of rice (Oryza sativa L.) cultivars, Taipie-309 (high photosynthetic-N and SUE) and Rasi (low photosynthetic-N and SUE) were investigated under high temperature stress (40 °C for 6 h). Plants exposed to high temperature stress caused significant reduction in photosynthetic activity, use efficiency of N and S, and increment in H2O2 and thiobarbituric acid reactive substance (TBARS) content. The drastic effects of high temperature stress were more pronounced in cultivar Rasi than Taipie-309. However, foliar spray of SNP decreased the high temperature induced H2O2 and TBARS content and increased accumulation of proline and activity of ascorbate–glutathione cycle that collectively improved tolerance to high temperature stress more effectively in Taipie-309. Exogenously applied SNP alleviated the high temperature induced decrease in photosynthesis through maintaining higher photosynthetic-NUE and photosynthetic-SUE, activity of ribulose 1,5 bisphosphate carboxylase/oxygenase (Rubisco), and synthesis of reduced glutathione (GSH). The use of 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxy-3-oxide (cPTIO, NO scavenger) substantiated the study that in the absence of NO oxidative stress increased, while NO increased photosynthetic-NUE and photosynthetic-SUE, net photosynthesis and plant dry mass. Taken together, the present investigation reveals that NO increased heat stress tolerance and minimized high temperature stress adversaries more effectively in cultivar Taipie-309 than Rasi by enhancing photosynthetic-NUE and SUE and strengthening the antioxidant defense system.

The emergence of multi-drug resistance in pathogenic bacteria in clinical settings as well as food-borne infections has become a serious health concern. The problem of drug resistance necessitates the need for alternative novel therapeutic strategies to combat this menace. One such approach is targeting the quorum-sensing (QS) controlled virulence and biofilm formation. In this study, we first screened different fractions of Psoralea corylifolia (seed) for their anti-QS property in the Chromobacterium violaceum 12472 strain. The methanol fraction was found to be the most active fraction and was selected for further bioassays. At sub-inhibitory concentrations, the P. corylifolia methanol fraction (PCMF) reduced QS-regulated virulence functions in C. violaceum CVO26 (violacein); Pseudomonas aeruginosa (elastase, protease, pyocyanin, chitinase, exopolysaccharides (EPS), and swarming motility), A. hydrophila (protease, EPS), and Serratia marcescens (prodigiosin). Biofilm formation in all the test pathogens was reduced significantly (p ≤ 0.005) in a concentration-dependent manner. The β-galactosidase assay showed that the PCMF at 1,000 μg/ml downregulated las-controlled transcription in PAO1. In vivo studies with C. elegans demonstrated increased survival of the nematodes after treatment with the PCMF. Bakuchiol, a phytoconstituent of the extract, demonstrated significant inhibition of QS-regulated violacein production in C. violaceum and impaired biofilm formation in the test pathogens. The molecular docking results suggested that bakuchiol efficiently binds to the active pockets of LasR and RhlR, and the complexes were stabilized by several hydrophobic interactions. Additionally, the molecular dynamics simulation of LasR, LasR–bakuchiol, RhlR, and RhlR–bakuchiol complexes for 50 ns revealed that the binding of bakuchiol to LasR and RhlR was fairly stable. The study highlights the anti-infective potential of the PCMF and bakuchiol instead of bactericidal or bacteriostatic action, as the extract targets QS-controlled virulence and the biofilm.

The worldwide dissemination of CTX-M type β-lactamases is a threat to human health. Previously, we have reported the spread of bla(CTX-M-15) gene in different clinical strains of Enterobacteriaceae from the hospital settings of Aligarh in north India. In view of the varying resistance pattern against cephalosporins and other β-lactam antibiotics, we intended to understand the correlation between MICs and catalytic activity of CTX-M-15. In this study, steady-state kinetic parameters and MICs were determined on E. coli DH5α transformed with bla(CTX-M-15) gene that was cloned from Enterobacter cloacae (EC-15) strain of clinical background. The effect of conventional β-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam) on CTX-M-15 was also studied. We have found that tazobactam is the best among these inhibitors against CTX-M-15. The inhibition characteristic of tazobactam is defined by its very low IC(50) value (6 nM), high affinity (K(i) = 0.017 µM) and better acylation efficiency (k(+2)/K' = 0.44 µM(-1)s(-1)). It forms an acyl-enzyme covalent complex, which is quite stable (k(+3) = 0.0057 s(-1)). Since increasing resistance has been reported against conventional β-lactam antibiotic-inhibitor combinations, we aspire to design a non-β-lactam core containing β-lactamase inhibitor. For this, we screened ZINC database and performed molecular docking to identify a potential non-β-lactam based inhibitor (ZINC03787097). The MICs of cephalosporin antibiotics in combination with this inhibitor gave promising results. Steady-state kinetics and molecular docking studies showed that ZINC03787097 is a reversible inhibitor which binds non-covalently to the active site of the enzyme through hydrogen bonds and hydrophobic interactions. Though, it's IC(50) (180 nM) is much higher than tazobactam, it has good affinity for CTX-M-15 (K(i) = 0.388 µM). This study concludes that ZINC03787097 compound can be used as seed molecule to design more efficient non-β-lactam containing β-lactamase inhibitor that could evade pre-existing bacterial resistance mechanisms.