Biology subjects

Kumar, A. H.

Publications and source records attributed to Kumar, A. H..

7 recordsLinked to original sources

bioRxiv2024

Network pharmacology of xylazine to understand its health consequences and develop mechanistic based remediations.

BackgroundThe recent raise in xylazine use disorders (XUD) in humans is a significant cause for concern as comprehensive understanding of its molecular pathology is limited and hence the ability to reverse the potential adverse effects are lacking. To address this gap, this study evaluates the dose-dependent impact of xylazine and its interactions with various potential targets, to identify an optimal reversal strategy. MethodsA trichotomized (Low, medium, and high) dose, volume of distribution and predicted plasma concentration of xylazine were defined. A detailed analysis of xylazines network protein targets and their tissue-specific expression was performed using classical pharmacoinformatic tools. Molecular docking was used to assess the drug-target affinities and identify potential reversal agents. ResultsThe study categorized xylazine plasma concentrations ranging from 5-8 M, 14-20 M, and 28-40 M, as low, medium, and high respectively. Xylazine displayed preferential affinity for hydrolases, kinases, transporters, and ion channels. Xylazines network analysis revealed the following proteins, ABCC9, RET, RAPGEF4, ACHE, TGFBR1, PGR, KCNH2, KCNN2, and TRPM8 as its high affinity targets. The tissue-specific expression of these high-affinity targets suggested potential adverse effects on various organs, particularly skeletal and smooth muscles, and the adrenal gland. The study further explored the potential reversal of xylazine pharmacology using alpha2AR-antagonists and CNS stimulants. Prazosin emerged as the most promising candidate, exhibiting a 200 to 2000-fold superior affinity against all high-affinity targets of xylazine. ConclusionThis study contributes to our understanding of xylazines molecular mechanisms and suggests that prazosin can serve as an effective therapeutic option for mitigating xylazine-induced adverse effects in XUD patients, which warrants clinical investigation.

pharmacology and toxicology↗

bioRxiv2024

Quantitative assessment of Newcastle disease virus proteins interactions with all known mucin types of Chicken and Quail

BackgroundNewcastle Disease (ND), caused by the Newcastle Disease Virus (NDV) poses a significant threat to poultry, leading to severe economic losses. Understanding the molecular interactions between NDV proteins and avian mucins is crucial for developing targeted interventions. Material and MethodsIn this study, twelve NDV proteins were systematically assessed for their interactions with sixteen quail and eight chicken mucin types, revealing diverse and species-specific binding patterns. ResultsHigh-affinity interactions between mucins (Muc5A, Muc5B, and Muc6) and NDV hemagglutinin-neuraminidase, was observed in addition to significant interactions with NDV fusion glycoprotein. Notably, chicken Muc4 displayed mid-range interactions exclusively with NDV fusion glycoprotein, highlighting potential species-specific differences in viral entry mechanisms between quails and chickens. Furthermore, the study investigated the number of binding sites on NDV proteins and chicken/quail mucins. Chicken Muc5B emerged as a standout with the highest number (20) of binding sites, suggesting its crucial role in NDV infection. The binding site analysis identified key regions in NDV fusion glycoprotein and hemagglutinin-neuraminidase, indicating potential targets for vaccine development. ConclusionThis study provides a foundation for future research into optimizing diagnostic approaches and therapeutic strategies for NDV infections. Validation of these interactions with real-world clinical data, coupled with an exploration of tissue-specific mucin expression patterns, could further enhance our understanding of host-virus dynamics. The identified interactions offer promising avenues for developing vaccines that target specific binding sites, thereby contributing to the effective control and prevention of Newcastle Disease in poultry populations.

microbiology↗

bioRxiv2023

Comprehensive Network and Structural Analysis of Bovine Papillomavirus, Squamous Cell Carcinoma Markers, and Elucidation of Efficacy Mechanisms of Phytochemicals from Thuja Occidentalis

Papillomaviruses infect cutaneous tissue in various species including bovines and from benign warts to malignant squamous cell carcinoma causing severe economic losses to the farmers. The mechanisms by which bovine papillomaviruses interact with host tissue are unclear. Hence in this study using classical network analysis tools, we evaluated interactions of Bovine papilloma (BPV) variants, with markers and receptors implicated in squamous cell carcinoma. Additionally, the thuja phytoconstituents were also evaluated for its potential to target the BPV and squamous cell carcinoma network interactions to understand the mechanism of its clinical benefits. Various protein composition of 14 different virus variants of BPV were assessed against 24 markers of squamous cell carcinoma. Among these interactions EGFR consistently exhibited high-affinity interactions with the E1 protein in all isoforms of BPV. Type 4 BPV displayed the maximum number of binding sites (14) with a binding pocket score ranging from 15.47 to 141.34 and a probability score of 0.75 to 0.99. The comparison of the binding pockets identified that BPV types 2 and 13 had the highest number of common amino acid sequences. Further the alpha helix structure of specific common amino acid sequences, contribute to a more robust and widespread affinity interaction with both E1 of various BPV types and EGFR. Analysis of thuja phytochemicals suggested superior efficacy of Beyerene and Terpinene-4-ol towards all ten BPV targets and bEGFR. In conclusion, our comprehensive study leading to identification of E1 protein of BPV as a major interacting network with bEGFR, their key binding sites, and efficacy of thuja phytoconstituents offer valuable insight into further experimental validation and development of novel therapeutic strategies against BPV-associated diseases.

pharmacology and toxicology↗

bioRxiv2023

Pharmacology of Berberine and its Metabolites, is it the natures Ozempic or Imatinib?

BackgroundBerberine, which is a naturally occurring alkaloid is widely explored for several health benefits including for weight management and metabolic disorders. The major pharmacological action of berberine is reported to be by activation of AMP-activated protein kinase, while its other clinical outcomes are devoid of clear mechanism of action/s. Hence in this study a detailed pharmacology of berberine and its two major metabolites (berberrubine, and jatrorrhizine) in humans was evaluated using well established Insilco tools. Materials and MethodsThe targets of berberine and its metabolites were identified in SwissTargetPrediction server and their affinity was assed using AutoDock vina 1.2.0. The binding pockets of the highest ligand receptor combinations was assessed using the PrankWeb: Ligand Binding Site Prediction tool. ResultsKinases, enzymes and family A GPCRs were identified as the top three target category of berberine and its metabolites. ROCK2, PIK3CD, KCNMA1, CSF1R and KIT were observed to be the high affinity targets of berberine and its metabolites with affinity values of <4 uM. The affinity of berberine and its metabolites against all AMPKs and lipid/glucose regulator targets (LDLR, DDP4 and PCSK9) were > 10 uM. The IC50 value of berberine and its metabolites against ROCK2 was the least (<1 uM), while their other high affinity targets (PIK3CD, KCNMA1, CSF1R and KIT) showed IC50 values < 5 uM. ConclusionThe diverse range of protein targets and the observed novel high affinity targets (ROCK2, PIK3CD, KCNMA1, CSF1R and KIT) offer valuable insights into the potential mechanisms of action and therapeutic effects of berberine and its metabolites in various disease conditions, which warrants validation in suitable efficacy analysis studies.

pharmacology and toxicology↗

bioRxiv2023

Network and structural analysis of quail mucins with expression pattern of MUC1 and MUC4 in the intestines of the Iraqi Common Quail (Coturnix Coturnix)

BackgroundMucins have vital pathophysiological role in gastrointestinal tract (GIT) of avian and other species. However, despite this very little is known about the types of mucins expressed in quail GIT. Hence in this study we examined the expression pattern of mucins (MUC1, and MUC4) in the GIT of the Iraqi Common Quail (Coturnix Coturnix) and performed the network and structural analysis of all reported types of mucins in various breeds of quails. Materials and methodsThis study protocol was approved by the animal ethics research committee of the College of Veterinary Medicine, University of Al-Qadisiyah, Iraq. Fresh samples of small and large intestines were used for histological and gene expression analysis of MUC1, and MUC4. Network and structural analysis of all reported types of mucins in quails was performed using the STRING Database, Chimera software and PrankWeb-Ligand Binding Site Prediction tool. ResultsThe histological analysis using Alcian blue and PAS stains indicated that most mucins in the intestines of quails were of the acidic mucin type, with minimal prevalence of neutral mucins. The expression of acidic mucins was relatively higher in the duodenum, ileum, caecum, and colon, while the jejunum showed a relatively higher expression of neutral mucins. Gene expression analysis revealed higher expression levels of MUC1 and MUC4 mRNA in the jejunum and colon, with its least expression in the duodenum and ilium. Network analysis indicated predominantly mucin-mucin interactions, with MUC 1, 15, 16 and 24 showing preferential homologous networks while the MUC 2, 4, 5 and 6 showed heterologous networks. Detailed evaluation of intermolecular hydrogen bond formation highlighted the interactions between specific mucin combinations, with certain combinations showing higher affinity, such as MUC5A-MUC6, MUC5A-MUC5B, and MUC5B-MUC6. In contrast, MUC15, MUC16, and MUC24 exhibited limited interactions with other mucin types. Binding site analysis indicated that MUC5B and MUC6 had the most number of binding sites with high probability scores, while MUC2, MUC4, and MUC5A showed lower probability scores despite having more binding sites. In contrast MUC 1, 15, and 16 had very few binding sites (<3 binding sites) all with very low probability scores. ConclusionThe findings of this study provide valuable insights into the composition, expression, network interactions, and binding sites of mucins in the quails, contributing to the understanding of mucin-related processes in gastrointestinal physiology and potential implications for gastrointestinal diseases.

physiology↗

bioRxiv2023

An assessment of the human Sortilin1 protein network, its expression and targetability using small molecules

BackgroundSortilin1 (SORT1) is a ubiquitously expressed transporter involved in sorting or clearing proteins and is pathologically linked to tissue fibrosis and calcification. Targeting SORT1 may have potential clinical efficacy in controlling or reversing cardiovascular fibrosis and/or calcification. Hence this study assessed the protein-protein network of human SORT1 and its targetability using small molecule nutra/pharmaceuticals. Material and methodsNetwork proteins of SORT1 in homo sapiens was identified using the String database, and the affinity of the protein-protein interaction of this network was analysed using Chimera software. The tissue specific expression profile of SORT1 was evaluated and assessed for enrichment in different cell types including the immune cells. A library of in-house small molecules and currently used therapeutics for cardiovascular diseases were screened using AutoDock vina to assess targetability of human SORT1. Concentration affinity (CA) ratio of the small molecules was estimated to assess the clinical feasibility of targeting SORT1. ResultsIGF2R, NTRK2, GRN and GGA1 were identified as high affinity interaction networks of SORT1. Of these high affinity interactions, IGF2R and GRN can be considered as relevant networks in regulating tissue fibrosis or microcalcification process due to their influence on T-cell activation, inflammation, wound repair, and tissue remodelling process. The tissue cell type enrichment indicated major expression of SORT1 in adipocytes, specialised epithelial cells, monocytes, cardiomyocytes, and thyroid glandular cells. The binding pocket analysis of human SORT1 showed twelve potential drug interaction sites with varying binding score (0.86 to 5.83) and probability of interaction (0.004 to 0.304). Five of the drug interaction sites were observed to be targetable at therapeutically feasible concentration of the small molecules evaluated. Empagliflozin, sitagliptin and lycopene showed superior affinity and CA ratio compared to established inhibitors of SORT1. ConclusionIGF2R and GRN are relevant networks of SORT1 regulating tissue fibrosis or microcalcification process. SORT1 can be targeted using currently approved small molecule therapeutics (empagliflozin and sitagliptin) or widely used nutraceutical (Lycopene) which should be evaluated in a randomised clinical trial to assess the efficacy to reduce cardiac/vascular microcalcification process.

pharmacology and toxicology↗

bioRxiv2023

A network pharmacology approach to assess the comparative pharmacodynamics of pharmaceutical excipient trehalose in human, mouse and rat

BackgroundTrehalose is used as a pharmaceutical excipient due to its several desirable pharmacokinetic and historically evident safety features. However, information on the pharmacodynamic properties of trehalose is lacking. Hence this study evaluated the comparative pharmacodynamic properties of trehalose using a network pharmacology approach. Materials and methodsThe specific targets of trehalose in human, mouse and rat were identified from the SwissTargetPrediction database, categorised and compared. The expression profile and subcellular localisation of the targets of trehalose in human was identified and correlated with the affinity of trehalose to these targets to assess its impact on the pharmacodynamic properties of trehalose. The affinity of trehalose to its metabolising enzyme in human, mouse, and rat was assessed by molecular docking and compared. ResultsA significant difference in the target categories and target types of trehalose was observed in human, mouse, and rat. The affinity of trehalose to human (66.03 {+/-} 5.1 M), rat (102.53 {+/-} 11.3 M) and mouse (42.07 {+/-} 5.3 M) trehalase was significantly different. Family A G protein coupled receptors were identified as the major target category of trehalose and cyclin dependent kinase 1 was observed as the high affinity target of trehalose in human and mouse. The correlation of target expression and affinity indicated minimal pharmacodynamic influence under physiological conditions. ConclusionThis study reports the selective targets of trehalose relevant to drug discovery and development protocols and highlights the limitations of rodent models in translating pharmacodynamic analysis of trehalose for development of human therapeutics.

pharmacology and toxicology↗