Identification of Novel Quinolone and Quinazoline Alkaloids as Phosphodiesterase 10A Inhibitors for Parkinson's Disease through a Computational Approach.

Phosphodiesterases (PDEs) are vital in signal transduction, specifically by hydrolyzing cAMP and cGMP. Within the PDE family, PDE10A is notable for its prominence in the striatum and its regulatory function over neurotransmitters in medium-spiny neurons. Given the dopamine deficiency in Parkinson's disease (PD) that affects striatal pathways, PDE10A inhibitors could offer therapeutic benefits by modulating D1 and D2 receptor signaling. This study was motivated by the successful history of quinazoline/quinazoline scaffolds in the inhibition of PDE10A. This study involved detailed in silico evaluations through docking followed by pharmacological, pharmacophoric, and pharmacokinetic analyses, prioritizing central nervous system (CNS)-active drug criteria. Seven cyclic peptides, those featuring the quinazoline/quinazoline moiety at both termini, exhibited notably enhanced docking scores compared to those of the remaining alkaloids within the screened library. We identified 7 quinolines and 1 quinazoline including Lepadin G, Aspernigerin, CJ-13536, Aurachin A, 2-Undecyl-4(1H)-quinolone, Huajiaosimuline 3-Prenyl-4-prenyloxyquinolin-2-one, and Isaindigotone that followed the standard CNS active drug criteria. The dominant quinoline ring in our study and its related quinazoline were central to our evaluations; therefore, the pharmacophoric features of these scaffolds were highlighted. The top alkaloids met all CNS-active drug properties; while nonmutagenic and without PAINS alerts, many indicated potential hepatotoxicity. Among the compounds, Huajiaosimuline was particularly significant due to its alignment with lead-likeness and CNS-active criteria. Aspernigerin demonstrated its affinity for numerous dopamine receptors, which signifies its potential to alter dopaminergic neurotransmission that is directly related to PD. Interestingly, the majority of these alkaloids had biological targets primarily associated with G protein-coupled receptors, critical in PD pathophysiology. They exhibit superior excretion parameters and toxicity end-points compared to the standard. Notably, selected alkaloids demonstrated stability in the binding pocket of PDE10A according to the molecular dynamic simulation results. Our findings emphasize the potential of these alkaloids as PDE10A inhibitors. Further experimental studies may be necessary to confirm their actual potency in inhibiting PDE10A before exploring their therapeutic potential in PD.

Decrypting the multi-genome data for chimeric vaccine designing against the antibiotic resistant Yersinia pestis.

Yersinia pestis, the causative agent of plague, is a gram-negative bacterium that can be fatal if not treated properly. Three types of plague are currently known: bubonic, septicemic, and pneumonic plague, among which the fatality rate of septicemic and pneumonic plague is very high. Bubonic plague can be treated, but only if antibiotics are used at the initial stage of the infection. But unfortunately, Y. pestis has also shown resistance to certain antibiotics such as kanamycin, minocycline, tetracycline, streptomycin, sulfonamides, spectinomycin, and chloramphenicol. Despite tremendous progress in vaccine development against Y. pestis, there is no proper FDA-approved vaccine available to protect people from its infections. Therefore, effective broad-spectrum vaccine development against Y. pestis is indispensable. In this study, vaccinomics-assisted immunoinformatics techniques were used to find possible vaccine candidates by utilizing the core proteome prepared from 58 complete genomes of Y. pestis. Human non-homologous, pathogen-essential, virulent, and extracellular and membrane proteins are potential vaccine targets. Two antigenic proteins were prioritized for the prediction of lead epitopes by utilizing reverse vaccinology approaches. Four vaccine designs were formulated using the selected B- and T-cell epitopes coupled with appropriate linkers and adjuvant sequences capable of inducing potent immune responses. The HLA allele population coverage of the T-cell epitopes selected for vaccine construction was also analyzed. The V2 constructs were top-ranked and selected for further analysis on the basis of immunological, physicochemical, and immune-receptor docking interactions and scores. Docking and molecular dynamic simulations confirmed the stability of construct V2 interactions with the host immune receptors. Immune simulation analysis anticipated the strong immune profile of the prioritized construct. In silico restriction cloning ensured the feasible cloning ability of the V2 construct in the expression system of E. coli strain K12. It is anticipated that the designed vaccine construct may be safe, effective, and able to elicit strong immune responses against Y. pestis infections and may, therefore, merit investigation using in vitro and in vivo assays.

In-silico evaluation of natural alkaloids against the main protease and spike glycoprotein as potential therapeutic agents for SARS-CoV-2.

Severe Acute Respiratory Syndrome Corona Virus (SARS-CoV-2) is the causative agent of COVID-19 pandemic, which has resulted in global fatalities since late December 2019. Alkaloids play a significant role in drug design for various antiviral diseases, which makes them viable candidates for treating COVID-19. To identify potential antiviral agents, 102 known alkaloids were subjected to docking studies against the two key targets of SARS-CoV-2, namely the spike glycoprotein and main protease. The spike glycoprotein is vital for mediating viral entry into host cells, and main protease plays a crucial role in viral replication; therefore, they serve as compelling targets for therapeutic intervention in combating the disease. From the selection of alkaloids, the top 6 dual inhibitory compounds, namely liensinine, neferine, isoliensinine, fangchinoline, emetine, and acrimarine F, emerged as lead compounds with favorable docked scores. Interestingly, most of them shared the bisbenzylisoquinoline alkaloid framework and belong to Nelumbo nucifera, commonly known as the lotus plant. Docking analysis was conducted by considering the key active site residues of the selected proteins. The stability of the top three ligands with the receptor proteins was further validated through dynamic simulation analysis. The leads underwent ADMET profiling, bioactivity score analysis, and evaluation of drug-likeness and physicochemical properties. Neferine demonstrated a particularly strong affinity for binding, with a docking score of -7.5025 kcal/mol for main protease and -10.0245 kcal/mol for spike glycoprotein, and therefore a strong interaction with both target proteins. Of the lead alkaloids, emetine and fangchinoline demonstrated the lowest toxicity and high LD50 values. These top alkaloids, may support the body's defense and reduce the symptoms by their numerous biological potentials, even though some properties naturally point to their direct antiviral nature. These findings demonstrate the promising anti-COVID-19 properties of the six selected alkaloids, making them potential candidates for drug design. This study will be beneficial in effective drug discovery and design against COVID-19 with negligible side effects.

Computer-aided identification of Mycobacterium tuberculosis resuscitation-promoting factor B (RpfB) inhibitors from Gymnema sylvestre natural products.

Tuberculosis (TB), an infectious disease caused by multi-drug resistant Mycobacterium tuberculosis (Mtb), has been a global health concern. Mtb affects over a third of the world's population, causing two million deaths annually due to its dormancy and propensity to spread infection during this period. Resuscitation-promoting factor B (RpfB) plays a pivotal role in the growth of Mtb during dormant periods, making it a critical target for eliminating Mtb and curing TB. Gymnema sylvestre is a famous medicinal plant with several medicinal properties, including antimicrobial activity; however, the therapeutic potential of the various reported metabolites of this plant against Mtb has not yet been explored. The aim of this study was to explore the reported natural products of G. sylvestre against the RpfB of the Mtb. A total of 131 reported secondary metabolites of this plant were collected and virtually screened against the RpfB. We particularly targeted the Glu292 residue of RpfB as it is crucial for the catalysis of this protein. From our in-house library, 114 compounds showed a binding affinity higher than the standard drug. The binding stability of the top three lead compounds was further confirmed through MD simulation analysis. Drug likeness analyses indicated that the ten hits had zero violations of the Lipinski rule of five. In addition, analyses of pharmacokinetics, toxicity, and target prediction revealed that the top compounds are devoid of toxicity and do not affect human proteins. Additionally, they reflect multifaceted approach as anti-TB agents. Our selected hits not only exhibit molecular properties favoring physiological compatibility but also exhibit properties enhancing their potential efficacy as therapeutic candidates. The compounds investigated here are worthy of experimental validation for the discovery of novel treatments against TB. Further, this study also provides a promising avenue for research on the pharmacological potential of G. sylvestre.

Mineral-Solubilizing Bacteria-Mediated Enzymatic Regulation and Nutrient Acquisition Benefit Cotton's (Gossypium hirsutum L.) Vegetative and Reproductive Growth.

Many farmers' incomes in developing countries depend on the cultivation of major crops grown in arid and semi-arid regions. The agricultural productivity of arid and semi-arid areas primarily relies on chemical fertilizers. The effectiveness of chemical fertilizers needs to improve by integration with other sources of nutrients. Plant growth-promoting bacteria can solubilize nutrients, increase plant nutrient uptake, and supplement chemical fertilizers. A pot experiment evaluated the promising plant growth-promoting bacterial strain's effectiveness in promoting cotton growth, antioxidant enzymes, yield, and nutrient uptake. Two phosphate solubilizing bacterial strains (Bacillus subtilis IA6 and Paenibacillus polymyxa IA7) and two zinc solubilizing bacterial strains (Bacillus sp. IA7 and Bacillus aryabhattai IA20) were coated on cotton seeds in a single as well as co-inoculation treatments. These treatments were compared with uninoculated controls in the presence and absence of recommended chemical fertilizer doses. The results showed the co-inoculation combination of Paenibacillus polymyxa IA7 and Bacillus aryabhattai IA20 significantly increased the number of bolls, seed cotton yield, lint yield, and antioxidants activities, including superoxide dismutase, guaiacol peroxidase, catalase, and peroxidase. Co-inoculation combination of Bacillus subtilis IA6 and Bacillus sp. IA16 promoted growth attributes, including shoot length, root length, shoot fresh weight, and root fresh weight. This co-inoculation combination also increased soil nutrient content. At the same time, Paenibacillus polymyxa IA7 + Bacillus aryabhattai IA20 increased nutrient uptake by plant shoots and roots compared.

Integrated use of phosphate-solubilizing Bacillus subtilis strain IA6 and zinc-solubilizing Bacillus sp. strain IA16: a promising approach for improving cotton growth.

Mineral nutrition of crop plants is one of the major challenges faced by modern agriculture, particularly in arid and semi-arid regions. In alkaline calcareous soils, the availability of phosphorus and zinc is critically less due to their fixation and precipitation as complexes. Farmers use fertilizers to fulfill crop requirements, but their efficacy is less, which increases production costs. Plant growth-promoting rhizobacteria (PGPR) can improve the availability of crop nutrients through solubilizing the insoluble compounds of phosphorus and zinc in soil. In the present study, a total of 40 rhizobacterial isolates were isolated from cotton rhizosphere and screened for improving cotton growth through the solubilization of phosphorus and zinc. Out of these 40 isolates, seven isolates (IA2, IA3, IA6, IA7, IA8, IA13, and IA14) efficiently solubilized insoluble rock phosphate while seven isolates (IA10, IA16, IA20, IA23, IA24, IA28, and IA30) were more efficient in solubilizing insoluble zinc oxide. In liquid media, strain IA7 (2.75 µg/mL) solubilized the highest amount of phosphate while the highest concentration of soluble zinc was observed in the broth inoculated with strain IA20 (3.94 µg/mL). Seven phosphate-solubilizing and seven zinc-solubilizing strains were evaluated using jar trial to improve the growth of cotton seedlings, and the results were quite promising. All the inoculated treatments showed improvement in growth parameters in comparison with control. Best results were shown by the combined application of IA6 and IA16, followed by the combination of strains IA7 and IA20. Based on the jar trial, the selected isolates were further characterized by plant growth-promoting characters such as siderophores production, HCN production, ammonia production, and exopolysaccharides production. These strains were identified through 16S rRNA sequencing as Bacillus subtilis IA6 (accession # MN005922), Paenibacillus polymyxa IA7 (accession # MN005923), Bacillus sp. IA16 (accession # MN005924), and Bacillus aryabhattai IA20 (accession # MN005925). It is hence concluded that the integrated use of phosphate-solubilizing and zinc-solubilizing strains as potential inoculants can be a promising approach for improving cotton growth under semi-arid conditions.

Preliminary study on phosphate solubilizing Bacillus subtilis strain Q3 and Paenibacillus sp. strain Q6 for improving cotton growth under alkaline conditions.

BACKGROUND: Low phosphorus availability limits crop production in alkaline calcareous soils in semi-arid regions including Pakistan. Phosphate solubilizing bacteria may improve crop growth on alkaline calcareous soils due to their ability to enhance P availability. METHODS: Twenty rhizobacterial isolates (Q1-Q20) were isolated from rhizosphere of cotton and characterized for their growth promoting attributes in vitro. The selected phosphate solubilizing isolates were further screened for their ability to improve cotton growth under axenic conditions (jar trial). The phosphorus solubilization capacities of selected strains were quantified and these strains were identified through 16S rDNA sequencing. RESULTS: Isolates Q2, Q3, Q6, Q7, Q8, Q13 and Q14 were able to solubilize phosphate from insoluble sources. Most of these isolates also possessed other traits including catalase activity and ammonia production. The growth promotion assay showed that Q3 was significantly better than most of the other isolates followed by Q6. Maximum root colonization (4.34 × 106 cfu g-1) was observed in case of isolate Q6 followed by Q3. The phosphorus solubilization capacities of these strains were quantified, showing a maximum phosphorus solubilization by Q3 (optical density 2.605 ± 0.06) followed by the Q6 strain. The strain Q3 was identified as Bacillus subtilis (accession # KX788864) and Q6 as Paenibacillus sp. (accession # KX788865) through 16S rDNA sequencing. DISCUSSION: The bacterial isolates varied in their abilities for different growth promoting traits. The selected PGPR Bacillus subtilis strain Q3 and Paenibacillus sp. strain Q6 have multifarious growth promoting traits including ability to grow at higher EC and pH levels, and phosphorus solubilizing ability. These strains can efficiently colonize cotton roots under salt affected soils and help plants in phosphorus nutrition. It is concluded that both strains are potential candidates for promoting cotton growth under alkaline conditions, however further investigation is required to determine their potential for field application.

Quinoline derivatives: candidate drugs for a class B G-protein coupled receptor, the calcitonin gene-related peptide receptor, a cause of migraines.

Class B G-protein coupled receptors are involved in a wide variety of diseases and are a major focus in drug design. Migraines are a common problem, and one of their major causative agents is the class B G-protein coupled receptor, Calcitonin gene-related peptide (CGRP) receptor, a target for competitive drug discovery. The calcitonin receptor-like receptor generates complexes with a receptor activity-modifying protein, which determines the type of receptor protein formed. The CGRP receptor comprises a complex formed from the calcitonin receptor-like receptor and receptor activity-modifying protein 1. In this study, an in silico docking approach was used to target the calcitonin receptor-like receptor in the bound form with receptor activity-modifying protein 1 (CGRP receptor), as well as in the unbound form. In both cases, the resulting inhibitors bound to the same cavity of the calcitonin receptor-like receptor. The twelve evaluated compounds were competitive inhibitors and showed efficient inhibitory activity against the CGRP receptor and Calcitonin receptor-like receptor. The two studied quinoline derivatives demonstrated potentially ideal inhibitory activity in terms of binding interactions and low range nano-molar inhibition constants. These compounds could prove helpful in designing drugs for the effective treatment of migraines. We propose that quinoline derivatives possess inhibitory activity by disturbing CGRP binding in the trigeminovascular system and may be considered for further preclinical appraisal for the treatment of migraines.

Nanoneurotoxicity to nanoneuroprotection using biological and computational approaches.

Nanoparticles (NPs) that are ∼100 nm in diameter can potentially cause toxicity in the central nervous system (CNS). Although NPs exhibit positive aspects, these molecules primarily exert negative or harmful effects. Thus, the beneficial and harmful effects should be compared. The prevalence of neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, and some brain tumors, has increased. However, the major cause of these diseases remains unknown. NPs have been considered as one of the major potential causes of these diseases, penetrating the human body via different pathways. This review summarizes various pathways for NP-induced neurotoxicity, suggesting the development of strategies for nanoneuroprotection using in silico and biological methods. Studies of oxidative stress associated with gene expression analyses provide efficient information for understanding neuroinflammation and neurodegeneration associated with NPs. The brain is a sensitive and fragile organ, and evolution has developed mechanisms to protect it from injury; however, this protection also hinders the methods used for therapeutic purposes. Thus, brain and CNS-related diseases that are the cause of disability and disorder are the most difficult to treat. There are many obstacles to drug delivery in the CNS, such as the blood brain barrier and blood tumor barrier. Considering these barriers, we have reviewed the strategies available to map NPs using biological techniques. The surface adsorption energy of NPs is the basic force driving NP gathering, protein corona formation, and many other interactions of NPs within biological systems. These interactions can be described using an approach named the biological surface adsorption index. A quantitative structural activity relationship study helps to understand different protein-protein or protein-ligand interactions. Moreover, equilibrium between cerebrovascular permeability is required when a drug is transferred via the circulatory system for the therapy of neurodegenerative diseases. Various drug delivery approaches, such as chemical drug delivery and carrier-mediated drug delivery, have been established to avoid different barriers inhibiting CNS penetration by therapeutic substances. Developing an improved understanding of drug receptors and the sites of drug action, together with advances in medicinal chemistry, will make it possible to design drugs with greatly enhanced activity and selectivity; this may result in a significant increase in the therapeutic index.