Muddassar, M. | Search bioRxiv

bioRxiv2024

Phytochemicals from Daucus carota have therapeutic potential against Triple-Negative Breast Cancer PDK1 and PLK1.

Triple-negative breast cancer (TNBC) is a deadly form of breast cancer that lacks estrogen, progesterone, and HER2 receptors. The development of drugs for TNBC has been challenging due to the lack of specific therapeutic targets. However, recent studies have shown that targeting the ATP active of the PDK-1 and PLK-1 proteins could be potential drug targets for TNBC treatment. New medications for TNBC have considerable adverse effects, highlighting the need for more targeted and effective therapies. In this study, we employed various computational approaches, including molecular docking, molecular dynamics (MD) simulations, pharmacokinetic studies, binding free energy calculations, principal component analysis (PCA), and alanine scanning analysis, to identify bioactive compounds from Daucus carota-extracted natural compounds that can bind to these ATP-binding sites and inhibit the activity of PDK1 and PLK1. Our study revealed that eight compounds showed reasonably good docking scores, binding free energies, and ADMET properties against the PDK1 and PLK1 enzymes. Astragalin and scolimoside showed substantial binding affinity and persistent interactions in the pocket region of the two proteins. Further MD simulation studies for 150 ns also suggested that the compounds were stably bound in the active site with very minor fluctuations. We believe that the identified hits for PDK1 and PLK1 from Daucus carota will be effective against TNBC in performing the biological assays.

bioinformatics↗

bioRxiv2022

Network Based Identification of Holistic Drug Target for Parkinson Disease and Deep Learning assisted Drug Repurposing.

Parkinson is a neurodegenerative disorder of the nervous system involved with disrupting the motor activity of the body. The current pathogenesis of the disorder is incomplete resulting in widespread use of exogenous medical treatments targeting the dopamine quantity, posing a major challenge in appropriate drug development. The plethora of high throughput techniques in the last decade has yielded a vast amount of Omics dataset with an opportunity of providing a holistic overview of the disease workings and dynamics. We integrated the Parkinson disease Omics datasets using network-based integration strategies to build Parkinson disease network. The most impactful and resilient node of the network was selected as a drug target. Deep learning based virtual screening estimator was built from physicochemical properties of different compounds having variable affinity to target binding. Virtual screening of FDA approved drugs repurposed 19 drugs with 25% of them falling under insomnia treatment; the most prevalent sleep disorder in Parkinson patients. Source Code of the project is available at https://github.com/aysanraza/pd_repurposing_protocol

bioinformatics↗

bioRxiv2022

Cross-sectional study of antimicrobial resistance and ecology in gastrointestinal and oral microbial communities of urban Pakistani adults

Background and AimsAntimicrobial resistance (AMR) is one of the most serious global public health threats affecting lower-middle-income countries (LMICs) due to lack of awareness, inadequate healthcare and sanitation infrastructure, plus other environmental factors. In this study, we aimed to link microbial assembly and covariates (body mass index, smoking, use of antibiotics) to gut microbiome structure and correlate AMR gene prevalence. MethodsWe examined the gastrointestinal and oral microbial profiles of healthy adults in Pakistan through 16S rRNA gene sequencing with a focus on different ethnicities, antibiotic usage, drinking water type, smoking, and other demographic measures. We then utilised a suite of innovative statistical tools, driven by numerical ecology and machine learning, to address the above aims. ResultsWe observed tap water as the main contributor for development of AMR in the Pakistani cohort. In addition, microbial niche breadth analysis based on null modelling procedures highlighted an aberrant gut microbial signature of smokers with increased age. ConclusionsDrinking water plays a more important role in AMR spread in Pakistan rather than other factors considered. Moreover, covariates such as smoking, and age impact the human microbial community structure in this Pakistani cohort. To the best of our knowledge, this is one of the first studies that provide a snapshot of the microbiomes of healthy individuals in Pakistan and considers AMR profiles with an emphasis on potential sources of AMR prevalence. Background and ContextPakistan is categorized as a low-and-middle-income country by the World Bank where misuse of antibiotics is widespread, and multidrug resistance is prevalent. Thus, it is imperative that we understand antimicrobial resistance and the drivers of human microbiomes in Pakistan. New FindingsIn a healthy Pakistani cohort, individuals that consumed Tap Water had almost 6-fold more associations with AMRs. Therefore, drinking water source could be a strong driver in the spread of AMR. LimitationsA limitation is the use of predictive functional profiles. However, shotgun metagenomics may be prohibitively costly for LMICs given the urgent need for AMR surveillance. Clinical Research RelevanceOur research shows strong associations of key microbial taxa with covariates such as age, BMI, and gender. Additionally, we show correlations between specific outlier taxa that are present both in the gut and oral communities, highlighting potential future feasibility for use of the oral microbiome as a proxy to gut dysbiosis in some cases. Basic Research RelevanceWe have applied recent advancements in analytical tools to link both AMR prevalence and human microbiome composition with factors such as age, BMI, gender, ethnicity, smoking status, use of antibiotics, and drinking water source. Additionally, we use null modelling to show that the microbial communities are subject to strong environmental pressure and dispersal limitation. Lay SummaryWe analysed gut and oral microbes from healthy individuals in Pakistan and found that the potential for antibiotic resistance was increased in those who drank tap water.

microbiology↗