Identification of Phytochemicals with Inhibitory Potential Against Beta-lactamase Enzymes via Computer-aided Approach.

INTRODUCTION: Antibacterial drugs have been widely used for the past century to treat diseases, but their efficacy has been limited by multi-resistant pathogens, particularly those that utilize beta-lactamase enzymes. The inhibition of beta-lactamase enzymes holds great promise for reducing the influence of such pathogens. OBJECTIVE: This study aims to evaluate the mechanism of inhibition of phytochemicals with antibacterial activity against two classes of beta-lactamases using computational methods. METHODS: To achieve this objective, a total of thirty phytochemicals were docked against SHV-1 beta-lactamase and AmpC beta-lactamase after procurement from Protein Data Bank. The pharmacokinetics (ADMET) and density functional theory (DFT) analysis study were also conducted to unravel the nature of the top six most promising compounds on each protein. RESULTS: The results showed that a significant percentage of the compounds had binding affinities greater than that of avibactam, the positive control. Quercetin-3-O-rutinoside showed the most promising results against SHV-1 beta-lactamase with an affinity of -9.4 kcal/mol, while luteolin was found to be the most promising candidate against AmpC beta-lactamase with an affinity of -8.5 kcal/mol. DFT analysis demonstrated the reactivity of these compounds, and the ADMET study indicated that they were relatively safe. CONCLUSION: In conclusion, the study's findings suggest that the selected compounds have significant potential to inhibit beta-lactamase and may be used in combination with antibiotics against organisms that produce beta-lactamase. This study provides a basis for further research in a wet-lab setting to validate the results.

Checkpoints and immunity in cancers: Role of GNG12.

Cancer progression is enhanced through cell proliferation, with the crucial role of the transducer and transmembrane -signal regulator (GNG12) bringing it to the fore. Dysregulation of cancer cell metabolism, evasion of the immune system, cell cycle, apoptosis, and chemoresistance result from inconsistent initiation of the NF-kB signaling pathway. We excerpt from previous studies that overactivation of the canonic NF-kB cascade occurs in varieties of tumor cells, which results in the growth of lymphovascular invasion, as well as neural invasion. Recently, research has adduced that a particular G protein- coupled receptor (GNG12) is silently involved in the activation of the NF-kB signal, which supports the evasion of cancer immunity and in turn activates cancer proliferation, angiogenesis, and immunotherapeutic resistance. While the likely impact of GNG12 in relation to the progression of tumors is being established, there is insufficient knowledge regarding the functions and mechanisms of GNG12 in cancer immunity. Furthermore, the cancer-associated role as well as the clinical correlation of GNG12 have long been unknown; thus, their identification is more likely to pave the path for a novel regime of tumor suppression. In this study, we established the silent role of GNG12 in activating NF-kB genes and the synergism between NF-kB and PD-L1 expression. Captivatingly, we reported that silencing GNG12 gene downregulates the transcription of PD-L1 gene. We therefore suggested that GNG12 is a risk factor for several cancers, and a possible target for immunotherapy.

In silico study revealed the inhibitory activity of selected phytomolecules of C. rotundus against VacA implicated in gastric ulcer.

Gastric ulcer is associated with weakening of the mucous coating of the stomach and damages to the intestinal lining. It is caused by H. pylori assisted by enzymes including VacA, which necessitates the need for inhibitors of VacA. Bioactive compounds from Cyperus rotundus have been documented to have anti-inflammatory activities. However, the mechanism of action of the phytochemicals is not characterized. This research aimed to assess, in silico, the potential of selected bioactive compounds against VacA based on the binding to its active sites. VacA and bioactive compounds structures were obtained from protein database and PubChem webserver, respectively. All compounds, including 2 controls, omeprazole and cimetidine were docked against the protein using AutoDock Vina and screened based on the binding energy. The selected complexes were subjected to pharmacokinetics and toxicity screening. Finally, molecular dynamics simulation and MMPBSA were carried out on two best compounds. 17 compounds interacted with the active site of VacA with higher binding affinities, with 7 of them - aureusidine, catechin, chlorogenic acid, isorhamnetin, isovitexin, oreintin, and vitexin having the best behaviours based on ADMET and druglikeness screening. Molecular dynamics and MMPBSA experiments of two of the hits corroborated good stability and binding energy for Ellagic Acid and Scirpusin B (ΔG = -14.38 and -13.20 kcal mol-1, respectively). These phytochemicals showed good pharmacokinetic profiles with respect to the control drugs. This study revealed that the identified compounds of C. rotundus may serve as VacA inhibitors and may be potent candidates for novel drug formulations in gastric ulcer treatment.Communicated by Ramaswamy H. Sarma.

Computational Evaluation of Azadirachta indica-Derived Bioactive Compounds as Potential Inhibitors of NLRP3 in the Treatment of Alzheimer's Disease.

BACKGROUND: The development of therapeutic agents against Alzheimer's disease (AD) has stalled recently. Drug candidates targeting amyloid-ß (Aß) deposition have often failed clinical trials at different stages, prompting the search for novel targets for AD therapy. The NLRP3 inflammasome is an integral part of innate immunity, contributing to neuroinflammation and AD pathophysiology. Thus, it has become a promising new target for AD therapy. OBJECTIVE: The study sought to investigate the potential of bioactive compounds derived from Azadirachta-indica to inhibit the NLRP3 protein implicated in the pathophysiology of AD. METHODS: Structural bioinformatics via molecular docking and density functional theory (DFT) analysis was utilized for the identification of novel NLRP3 inhibitors from A. indica bioactive compounds. The compounds were further subjected to pharmacokinetic and drug-likeness analysis. Results obtained from the compounds were compared against that of oridonin, a known NLRP3 inhibitor. RESULTS: The studied compounds optimally saturated the binding site of the NLRP3 NACHT domain, forming principal interactions with the different amino acids at its binding site. The studied compounds also demonstrated better bioactivity and chemical reactivity as ascertained by DFT analysis and all the compounds except 7-desacetyl-7-benzoylazadiradione, which had two violations, conformed to Lipinski's rule of five. CONCLUSION: In silico studies show that A. indica derived compounds have better inhibitory potential against NLRP3 and better pharmacokinetic profiles when compared with the reference ligand (oridonin). These compounds are thus proposed as novel NLRP3 inhibitors for the treatment of AD. Further wet-lab studies are needed to confirm the potency of the studied compounds.

Discovery of potential HER2 inhibitors from Mangifera indica for the treatment of HER2-Positive breast cancer: an integrated computational approach.

Human epidermal growth factor receptor 2 (HER2) is a member of epidermal growth factor receptors with tyrosine kinase functionality. The dimerization of HER2 leads to the autophosphorylation of tyrosine residues within its cytoplasmic domain, resulting in hyperactivation of several downstream signal transduction pathways that play an important role in tumorigenesis, cancer aggressiveness and cell proliferation. Amplification or overexpression of HER2 has been found in approximately 15-30% of breast cancers. Hence, HER2 serve as a therapeutic biomarker in breast cancer. Herein, we applied structural bioinformatics techniques via molecular docking, molecular dynamics simulations, Molecular mechanics/generalized Born surface area (MM/GBSA) calculations and pharmacokinetic models to identify putative HER2 inhibitors. Application of stringent molecular docking results in the identification of bioactive compounds from Mangifera indica as selective, potent inhibitors of HER2. However, only the top three compounds with the highest negative docking score (< -9kcal/mol) was considered in reference to neratinib (-8.601 kcal/mol) for computational analysis. The molecular dynamics simulations and post-simulation analysis of docked HER2-ligand complexes unveil the substantial stability for M. indica ligands over the 100 ns simulation period. Additionally, MM/GBSA binding free energy calculation supports the inhibitory potential for the docked ligands, which exclusively revealed the highest binding energy for selected M. indica ligands than the reference compound (neratinib). The pharmacokinetic model showed that M. indica ligands are promising therapeutic agents. Conclusively, bioactive compounds from M. indica may serve as lead molecules that could be developed into potent and effective HER2 inhibitors for breast cancer treatment.Communicated by Ramaswamy H. Sarma.

Identification of Terpenoids From Abrus precatorius Against Parkinson's Disease Proteins Using In Silico Approach.

Parkinson's disease (PD) is the second major neuro-degenrative disorder that causes morbidity and mortality among older populations. Terpenoids were reported as potential neuro-protective agents. Therefore, this study seeks to unlock the inhibitory potential of terpenoids from Abrus precatorius seeds against proteins involve in PD pathogenesis. In this study, in silico molecular docking of 5 terpenoids derived from high-performance liquid chromatography (HPLC) analysis of A. precatorius seeds against α-synuclein, catechol-o-methyltransferase, and monoamine oxidase B which are markers of PD was performed using Autodock vina. The absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) of the hits were done using Swiss ADME predictor and molecular dynamic (MD) simulation of the hit-protein complex was performed using Desmond Schrodinger software. Five out of 6 compounds satisfied the ADME/Tox parameters and showed varying degrees of binding affinities with selected proteins. Drimenin-α-synuclein complex showed the lowest binding energy of -9.1 kcal/mol followed by interaction with key amino acid residues necessary for α-synuclein inhibition. The selection of this complex was justified by its stability in MD simulation conducted for 10 ns and exhibited stable interaction in terms of root mean square deviation (RMSD) and root mean square deviation error fluctuation (RMSF) values.

Computational prediction of nimbanal as potential antagonist of respiratory syndrome coronavirus.

The high pathogenic nature of the Middle East Respiratory coronavirus (MER) and the associated high fatality rate demands an urgent attention from researchers. Because there is currently no approved drug for the management of the disease, research efforts have been intensified towards the discovery of a potent drug for the treatment of the disease. Papain Like protease (PLpro) is one of the key proteins involved in the viral replication. We therefore docked forty-six compounds already characterized from Azadirachta indica, Xylopia aethipica and Allium cepa against MERS-CoV-PLpro. The molecular docking analysis was performed with AutoDock 1.5.6 and compounds which exhibit more negative free energy of binding, and low inhibition constant (Ki) with the protein (MERS-CoV-PLpro) were considered potent. The physicochemical and pharmacokinetic properties of the compounds were predicted using the Swissadme web server. Twenty-two of the compounds showed inhibition potential similar to dexamethasone and remdesvir, which had binding affinity of -6.8 and -6.3 kcal/mol respectively. The binding affinity of the compounds ranged between -3.4 kcal/mol and -7.7 kcal/mol whereas; hydroxychloroquine had a binding affinity of -4.5 kcal/mol. Among all the compounds, nimbanal and verbenone showed drug likeliness, they did not violate the Lipinski rule neither were they inhibitors of drug-metabolizing enzymes. Both nimbanal and verbenone were further post-scored with MM/GBSA and the binding free energy of nimbanal (-25.51 kcal/mol) was comparable to that of dexamethasone (-25.46 kcal/mol). The RMSD, RMSF, torsional angle, and other analysis following simulation further substantiate the efficacy of nimbanal as an effective drug candidate. In conclusion, our study showed that nimbanal is a more promising therapeutic agent and could be a lead for the discovery of a new drug that may be useful in the management of severe respiratory coronavirus syndrome.