Repurposing of FDA approved drugs and their validation against potential drug targets for Salmonella enterica through molecular dynamics simulation

Structural and molecular basis of the interaction mechanism of selected drugs towards multiple targets of SARS-CoV-2 by molecular docking and dynamic simulation studies- deciphering the scope of repurposed drugs

Typhoid and paratyphoid fever may follow a seasonal pattern, but this pattern is not well characterized. Moreover, the environmental drivers that influence seasonal dynamics are not fully understood, although increasing evidence suggests that rainfall and temperature may play an important role. We compiled a database of typhoid, paratyphoid, or enteric fever and their potential environmental drivers. We assessed the seasonal dynamics by region and latitude, quantifying the mean timing of peak prevalence and seasonal variability. Moreover, we investigated the potential drivers of the seasonal dynamics and compared the seasonal dynamics for typhoid and paratyphoid fever. We observed a distinct seasonal pattern for enteric and typhoid fever by latitude, with seasonal variability more pronounced further from the equator. We also found evidence of a positive association between preceding rainfall and enteric fever among settings 35°–11°N and a more consistent positive association between temperature and enteric fever incidence across most regions of the world. In conclusion, we identified varying seasonal dynamics for enteric or typhoid fever in association with environmental factors. The underlying mechanisms that drive the seasonality of enteric fever are likely dependent on the local context and should be taken into account in future control efforts.

During the late stages of infection, Salmonella secretes numerous effectors through a type III secretion system that is encoded within Salmonella pathogenicity island 2 (SPI2). Despite the importance of SPI2 as a major virulence factor leading to the systemic spread of the bacteria and diseases, a global view of its effects on host responses is still lacking. Here, we measured global impacts of SPI2 effectors on the host phosphorylation and protein expression levels in RAW264.7 and in HeLa cells, as macrophage and nonphagocytic models of infection. We observe that SPI2 effectors differentially modulate the host phosphoproteome and cellular processes (e.g. protein trafficking, cytoskeletal regulation, and immune signaling) in a host cell-dependent manner. Our unbiased approach reveals the involvement of many previously unrecognized proteins, including E3 ligases (HERC4, RanBP2, and RAD18), kinases (CDK, SIK3, and WNK1), and histones (H2B1F, H4, and H15), in late stages of Salmonella infection. Furthermore, from this phosphoproteome analysis and other quantitative screens, we identified HSP27 as a direct in vitro and in vivo molecular target of the only type III secreted kinase, SteC. Using biochemical and cell biological assays, we demonstrate that SteC phosphorylates multiple sites in HSP27 and induces actin rearrangement through this protein. Together, these results provide a broader landscape of host players contributing to specific processes/pathways mediated by SPI2 effectors than was previously appreciated.

NEK7 is a NIMA related-protein kinase that plays a crucial role in spindle assembly and cell division. Dysregulation of NEK7 protein leads to development and progression of different types of malignancies including colon and breast cancers. Therefore, NEK7 could be considered as an attractive target for anti-cancer drug discovery. However, few efforts have been made for the development of selective inhibitors of NIMA-related kinase but still no FDA approved drug is known to selectively inhibit the NEK7 protein. Dacomitinib and Neratinib are two Enamide derivatives that were approved for treatment against non-small cell lung cancer and breast cancer respectively. Drug repurposing is a time and cost-efficient method for re-evaluating the activities of previously authorized medications. Thus, the present research involves the repurposing of two FDA-approved medications via comprehensive in silico approach including Density functional theory (DFTs) studies which were conducted to determine the electronic properties of the Dacomitinib and Neratinib. Afterward, binding orientation of selected drugs inside NEK7 activation loop was evaluated through molecular docking approach. Selected drugs exhibited potential molecular interactions engaging important amino acid residues of active site. The docking score of Dacomitinib and Neratinib was –30.77 and –26.78 kJ/mol, respectively. The top ranked pose obtained from molecular docking was subjected to Molecular Dynamics (MD) Simulations for investigating the stability of protein-ligand complex. The RMSD pattern revealed the stability of protein-ligand complex throughout simulated trajectory. In conclusion, both drugs displayed inhibitory efficacy against NEK7 protein and provide a prospective therapy option for malignant malignancies linked with NEK7.

The proportion of paratyphoid fever cases to typhoid fever cases may change due to urbanization and increased dependency on food purchased from street vendors. For containment of paratyphoid a different strategy may be needed than for typhoid, because risk factors for disease may not coincide and current typhoid vaccines do not protect against paratyphoid fever. To determine risk factors for typhoid and paratyphoid fever in an endemic area. Community-based case-control study conducted from June 2001 to February 2003 in hospitals and outpatient health centers in Jatinegara district, Jakarta, Indonesia. Enrolled participants were 1019 consecutive patients with fever lasting 3 or more days, from which 69 blood culture-confirmed typhoid cases, 24 confirmed paratyphoid cases, and 289 control patients with fever but without Salmonella bacteremia were interviewed, plus 378 randomly selected community controls. Blood culture-confirmed typhoid or paratyphoid fever; risk factors for both diseases. In 1019 fever patients we identified 88 (9%) Salmonella typhi and 26 (3%) Salmonella paratyphi A infections. Paratyphoid fever among cases was independently associated with consumption of food from street vendors (comparison with community controls: odds ratio [OR], 3.34; 95% confidence interval [CI], 1.41-7.91; with fever controls: OR, 5.17; 95% CI, 2.12-12.60) and flooding (comparison with community controls: OR, 4.52; 95% CI, 1.90-10.73; with fever controls: OR, 3.25; 95% CI, 1.31-8.02). By contrast, independent risk factors for typhoid fever using the community control group were mostly related to the household, ie, to recent typhoid fever in the household (OR, 2.38; 95% CI, 1.03-5.48); no use of soap for handwashing (OR, 1.91; 95% CI, 1.06-3.46); sharing food from the same plate (OR, 1.93; 95% CI, 1.10-3.37), and no toilet in the household (OR, 2.20; 95% CI, 1.06-4.55). Also, typhoid fever was associated with young age in years (OR, 0.96; 95% CI, 0.94-0.98). In comparison with fever controls, risk factors for typhoid fever were use of ice cubes (OR, 2.27; 95% CI, 1.31-3.93) and female sex (OR, 1.79; 95% CI, 1.04-3.06). Fecal contamination of drinking water was not associated with typhoid or paratyphoid fever. We did not detect fecal carriers among food handlers in the households. In Jakarta, typhoid and paratyphoid fever are associated with distinct routes of transmission, with the risk factors for disease either mainly within the household (typhoid) or outside the household (paratyphoid).

BackgroundTyphoid and paratyphoid fever are common infectious diseases and remain a heavy burden, especially in some low-income countries. Although the global burden has decreased over the past three decades, an analysis of the burden of typhoid and paratyphoid fever will help inform public health strategies.MethodsThis study is aimed to comprehensively evaluate the global, regional, and national burden of typhoid and paratyphoid, and the temporal trends while exploring potential associations with socio-demographic development over three decades (1990–2021). Data on typhoid and paratyphoid fever were analyzed using the Global Burden of Disease (GBD) study in 2021. For this analysis, we calculated to demonstrate temporal trends in the incidence, mortality, and disability adjusted life years (DALYs) of typhoid and paratyphoid fever from 1990 to 2021.ResultsFrom 1990 to 2021, both typhoid and paratyphoid fever showed declining trends globally and in different socio-demographic index (SDI) regions, including incidence, mortality, and DALYs. For typhoid fever worldwide, new cases decreased by 62.12%, with an EAPC of -3.92 (-4.14, -3.71); deaths decreased by 50.65%, EAPC − 2.83 (-2.99, -2.66), and DALYs decreased by 52.30%, EAPC − 2.82 (-3.00, -2.64). For paratyphoid fever, new cases decreased by 73.15%, with an EAPC of -4.77 (-5.29, -4.26); deaths decreased by 65.44%, EAPC − 3.74 (-4.24, -3.24), and DALYs decreased by 68.42%, EAPC − 3.87 (-4.42, -3.31). For both typhoid and paratyphoid fever, children had the highest morbidity and mortality rates; males had higher rates of incidence, mortality, and DALYs than females. However, among older patients, the absolute number of new cases and DALYs was higher in women. The burden is concentrated in South Asia, Southeast Asia, and Oceania, with only South Asia suffering severely from paratyphoid fever. Regarding typhoid fever, the top three countries with the highest ASRs of incidence are Burkina Faso (328.48) (SDI: 0.285), Bangladesh (303.14) (SDI: 0.492), and Papua New Guinea (299.45) (SDI: 418) which are in Western Sub-Saharan, South Asia, and Oceania. The top three countries in terms of mortality and DALYs are Bhutan (5.61; 434.23) (SDI: 0.473), Bangladesh (5.06; 382.38), and Burkina Faso (4.64; 352.57). Regarding paratyphoid fever, the top three countries with the highest ASRs of mortality and DALYs are the same, including Pakistan (1.05; 72.66), India (0.75; 53.42), and Nepal (0.72; 50.65) (SDI: 0.433), all of which are located in South Asia.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12879-025-11223-8.

Reprofiling analysis of FDA approved drugs with upregulated differential expression genes found in hypertension

Chapter 71 - Salmonella Typhi and Salmonella Paratyphi A

Type 2 diabetes mellitus is a chronic health problem that can be controlled by slowing one's carbohydrate metabolism by inhibiting α-glucosidase, an enzyme responsible for carbohydrate degradation. Currently, drugs for type 2 diabetes have limitations in terms of safety, efficiency, and potency, while cases are rapidly increasing. For this reason, the study planned and moved towards drug repurposing by utilizing food and drug administration (FDA)-approved drugs against α-glucosidase, and investigated the molecular mechanisms. The target protein was refined and optimized by introducing missing residues, and minimized to remove clashes to find the potential inhibitor against α-glucosidase. The most active compounds were selected after the docking study to generate a pharmacophore query for the virtual screening of FDA-approved drug molecules based on shape similarity. The analysis was performed using Autodock Vina (ADV)-based on binding affinities (-8.8 kcal/mol and -8.6 kcal/mol) and root-mean-square-deviation (RMSD) values (0.4 Å and 0.6 Å). Two of the most potent lead compounds were selected for a molecular dynamics (MD) simulation to determine the stability and specific interactions between receptor and ligand. The docking score, RMSD values, pharmacophore studies, and MD simulations revealed that two compounds, namely Trabectedin (ZINC000150338708) and Demeclocycline (ZINC000100036924), are potential inhibitors for α-glucosidase compared to standard inhibitors. These predictions showed that the FDA-approved molecules Trabectedin and Demeclocycline are potential suitable candidates for repurposing against type 2 diabetes. The in vitro studies showed that trabectedin was significantly effective with an IC50 of 1.263 ± 0.7 μM. Further investigation in the laboratory is needed to justify the safety of the drug to be used in vivo.

Exploring the new therapeutic indications of known drugs for treating COVID-19, popularly known as drug repurposing, is emerging as a pragmatic approach especially owing to the mounting pressure to control the pandemic. Targeting multiple targets with a single drug by employing drug repurposing known as the polypharmacology approach may be an optimised strategy for the development of effective therapeutics. In this study, virtual screening has been carried out on seven popular SARS-CoV-2 targets (3CLpro, PLpro, RdRp (NSP12), NSP13, NSP14, NSP15, and NSP16). A total of 4015 approved drugs were screened against these targets. Four drugs namely venetoclax, tirilazad, acetyldigitoxin, and ledipasvir have been selected based on the docking score, ability to interact with four or more targets and having a reasonably good number of interactions with key residues in the targets. The MD simulations and MM-PBSA studies showed reasonable stability of protein-drug complexes and sustainability of key interactions between the drugs with their respective targets throughout the course of MD simulations. The identified four drug molecules were also compared with the known drugs namely elbasvir and nafamostat. While the study has provided a detailed account of the chosen protein-drug complexes, it has explored the nature of seven important targets of SARS-CoV-2 by evaluating the protein-drug complexation process in great detail.Graphical abstractDrug repurposing strategy against SARS-CoV2 drug targets. Computational analysis was performed to identify repurposable approved drug candidates against SARS-CoV2 using approaches such as virtual screening, molecular dynamics simulation and MM-PBSA calculations. Four drugs namely venetoclax, tirilazad, acetyldigitoxin, and ledipasvir have been selected as potential candidates. Supplementary InformationThe online version contains supplementary material available at 10.1007/s12039-022-02046-0.

Phytochemicals are bioactive agents present in medicinal plants with therapeutic values. Phytochemicals isolated from plants target multiple cellular processes. In the current work, we have used fractionation techniques to identify 13 bioactive polyphenols in ayurvedic medicine Haritaki Churna. Employing the advanced spectroscopic and fractionation, structure of bioactive polyphenols was determined. Blasting the phytochemical structure allow us to identify a total of 469 protein targets from Drug bank and Binding DB. Phytochemicals with their protein targets from Drug bank was used to create a phytochemical-protein network comprising of 394 nodes and 1023 edges. It highlights the extensive cross-talk between protein target corresponding to different phytochemicals. Analysis of protein targets from Binding data bank gives a network comprised of 143 nodes and 275 edges. Taking the data together from Drug bank and binding data, seven most prominent drug targets (HSP90AA1, c-Src kinase, EGFR, Akt1, EGFR, AR, and ESR-α) were found to be target of the phytochemicals. Molecular modelling and docking experiment indicate that phytochemicals are fitting nicely into active site of the target proteins. The binding energy of the phytochemicals were better than the inhibitors of these protein targets. The strength and stability of the protein ligand complexes were further confirmed using molecular dynamic simulation studies. Further, the ADMET profiles of phytochemicals extracted from HCAE suggests that they can be potential drug targets. The phytochemical cross-talk was further proven by choosing c-Src as a model. HCAE down regulated c-Src and its downstream protein targets such as Akt1, cyclin D1 and vimentin. Hence, network analysis followed by molecular docking, molecular dynamics simulation and in-vitro studies clearly highlight the role of protein network and subsequent selection of drug candidate based on network pharmacology. Communicated by Ramaswamy H. Sarma

De novo design and bioactivity prediction of mitotic kinesin Eg5 inhibitors using MPNN and LSTM-based transfer learning.

COVID-19, caused by novel coronavirus or SARS-CoV-2, is a viral disease which has infected millions worldwide. Considering the urgent need of the drug for fighting against this infectious disease, we have performed in-silico drug repurposing followed by molecular dynamics (MD) simulation and MM-GBSA calculation. The main protease (Mpro) is one of the best-characterized drug targets among coronaviruses, therefore, this was screened for already known FDA approved drugs and some natural compounds. Comparison of docking and MD simulation results of complexes of drugs with that of inhibitor N3 (experimentally obtained) suggests EGCG, withaferin, dolutegravir, artesunate as potential inhibitors of the main protease (Mpro). Further, in silico docking and MD simulation suggest that EGCG analogues ZINC21992196 and ZINC 169337541 may act as a better inhibitor. Communicated by Ramaswamy H. Sarma

The kynurenine pathway (KP) plays a pivotal role in dampening the immune response in many types of cancer, including TNBC. The intricate involvement of tryptophan degradation via KP serves as a critical regulator in mediating immunosuppression in the tumor microenvironment. The key enzymes that facilitate this mechanism and contribute to tumor progression are indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO). Despite attempts to use navoximod as a dual-specific inhibitor, its poor bioavailability and lack of clinical efficacy have hampered its utility. To date, no FDA-approved drugs have advanced for dual targeting of these enzymes. Therefore, this study aimed to repurpose the approved drugs from the DrugBank database as novel IDO1/TDO inhibitors. Initially, 2588 FDA-approved compounds were screened by employing molecular docking and pharmacokinetic profiling. Subsequently, methods such as MM-GBSA calculations and machine learning based analysis precisely identified 20 potential lead compounds. The resultant compounds were then assessed for various toxicity endpoints and anticancer activity. The PaccMann server revealed potent anticancer activity, with sensitivities ranging from 0.203 to 24.119 μM against MDA-MB-231 TNBC cell lines. Alongside, the interaction profile with critical residues, strongly reinforced DB06292 (Dapagliflozin) as a compelling hit candidate. Finally, the reliability of the result was corroborated through a rigorous 200 ns molecular dynamics simulation, ensuring the stable binding of the hit against the target proteins. Considering the promising outcomes, we speculate that the proposed hit compound holds strong potential for the management of TNBC.

Background/Objectives: Eumycetoma, caused by Madurella mycetomatis, is a chronic fungal infection with limited treatment options and increasing drug resistance. CYP51, a key enzyme in ergosterol biosynthesis, is a well-established target for azole antifungals. However, existing azole drugs demonstrate limited efficacy in treating eumycetoma. Microbial-based natural products, with their structural diversity and bioactivity, offer a promising source for novel CYP51 inhibitors. This study aimed to identify potential Madurella mycetomatis CYP51 inhibitors from microbial natural products using molecular docking, MM-GBSA calculations, ADMET analysis, and molecular dynamics (MD) simulations. Methods: Virtual screening was conducted on a library of microbial-based natural products using an in-house homology model of Madurella mycetomatis CYP51, with itraconazole as the reference drug. The top compounds from initial docking were refined through Standard and Extra Precision docking. MM-GBSA calculations assessed binding affinities, and ADMET analysis evaluated drug-like properties. Compounds with favorable properties underwent MD simulations. Results: The computational investigations identified 34 compounds with better docking scores and binding affinity than itraconazole. Of these, 9 compounds interacted with the heme group and key residues in the active site of Madurella mycetomatis CYP51. In silico pharmacokinetic profiling identified 3 compounds as promising candidates, and MD simulations confirmed their potential as CYP51 inhibitors. Conclusions: The study highlights microbial-derived natural products, particularly monacyclinone G, H, and I, as promising candidates for Madurella mycetomatis CYP51 inhibition, with the potential for treating eumycetoma, requiring further experimental validation.