Biology subjects

Siddiqi, M. I.

Publications and source records attributed to Siddiqi, M. I..

4 recordsLinked to original sources

bioRxiv2026

Identification of Novel Inhibitors of JEV RdRp as Potent Antiviral Drugs: Targeting NS5-NS3 Protein Interaction

Japanese Encephalitis Virus (JEV) belongs to the Flavivirus family, and the RNA dependent RNA polymerase (RdRp) domain located at the C terminus of non structural protein 5 (NS5) regulates de novo viral genome synthesis. The conserved priming loop inserted in the thumb domain of RDRP initiates de novo genome synthesis. Interestingly, the reported replication process initiates with an interaction between NS5 (methyltransferase/RDRP) and NS3 (protease/helicase), and inhibiting this interaction directly correlates with the inhibition of viral replication. The function of the priming loop in the context of the NS5 NS3 interaction is not yet known. In this study, we studied the priming loop function in the NS5 NS3 interaction and viral replication. Using a structure based drug design approach, we screened the Maybridge compound library against the RdRp priming loop and identified 15 candidate compounds based on binding energy. Among them, DSHS00151 showed significant dose dependent inhibition of the NS5 NS3 interaction with an IC50 of 3.5 micromolar in the mammalian two hybrid assay, inhibited viral infectivity with an IC50 of 2.54 micromolar, and reduced viral RNA load with an IC50 of 2.9 micromolar, compared to CD10712. Molecular Dynamics (MD) simulations revealed that DSHS00151 exhibits stronger and more stable binding with the priming loop residues (790 to 812) compared to CD10712. The molecular mechanism suggested by the docking of the NS5 and NS3 proteins showed that the priming loop tends to rotate toward the NS3 protein to stabilize the complex, and compound binding restricts this loop rotation, thus compromising the stability of the NS5 and NS3 complex and affecting viral replication. Overall, our study validated the function of the NS5 priming loop as an allosteric site, and compounds binding to this allosteric site belong to the Non Nucleoside Reverse Transcriptase Inhibitors (NNRTI) class of inhibitors, which disrupt the NS5 and NS3 interaction and could be developed as novel anti JEV therapeutics.

pathology↗

bioRxiv2023

Leveraging RAS-mSIN1 Interaction to Selectively Inhibit mTORC2 Employing Competitive RAS Binding Peptide: Implications in Breast Cancer Metastasis

StatementThe authors have withdrawn their manuscript owing to the authors decision of withdrawing of the manuscript until all experiments are completed. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

cancer biology↗

bioRxiv2023

Salmonella Typhimurium effector SseI regulates host peroxisomal dynamics to acquire lysosomal cholesterol for better intracellular growth

Intracellular Salmonella resides and multiplies in cholesterol-rich specialized compartment called Salmonella-containing vacuoles (SCVs) and avoids fusion with acidic lysosomes. Given, lysosomes are primary organelle that redistributes LDL derived cholesterol to other organelles; we questioned how lysosomal cholesterol can be transported to SCV. We demonstrate here that peroxisomes are recruited to SCVs in human primary macrophages, epithelial cells and functions as pro-bacterial organelles. Further, this interaction is assisted by SseI, a Salmonella effector protein containing mammalian peroxisome targeting sequence. SseI localizes to peroxisome, interacts and activates a host Ras GTPase, ARF-1 on the peroxisome membrane. Activation of ARF-1 leads to recruitment of phosphatidylinsolitol-5- phosphate-4 kinase to generate phosphatidylinsolitol-4-5-bisphosphate on peroxisomes. Accordingly, the{Delta} sseI strain showed reduced virulence in cell lines and during mice infection. Taken together, our work identified a fascinating mechanism by which a pathogen targets host organelles via its secretory effectors and exploits host metabolic intermediates for its intracellular proliferation.

cell biology↗

bioRxiv2017

Mathematical Model For Plant-Insect Interaction With Dynamic Response To PAD4-BIK1 Interaction And Effect Of BIK1 Inhibition

Plant-insect interaction system has been a widely studied model of the ecosystem. Attempts have long been made to understand the numerical behaviour of this counter system and make improvements in it from initial simple analogy based approach with predator-prey model to the recently developed mathematical interpretation of plant-insect interaction including concept of plant immune interventions Caughley and Lawton (1981). In our current work, we propose an improvement in the model, based on molecular interactions behind plant defense mechanism and its effect on the plant growth and insect herbivory. Motivated from an interaction network of plant biomolecules given by Louis and Shah (2014) and extending the model of Chattopadhyay, et al (2001), we propose here a mathematical model to show how plant insect interaction system is governed by the molecular components inside. Insect infestation mediated induction of Botrytis Induced Kinase-1 (BIK-1) protein causes inhibition of Phyto Alexin Deficient-4 (PAD4) protein. Lowered PAD4, being responsible for initiating plant defense mechanism, results in degraded plant immune potential and thus causes loss of plant quality. We adapt these interactions in our model to show how they influence the plant insect interaction system and also to reveal how silencing BIK-1 may aid in enhanced production of plant biomass by increasing plant immunity mediated by increase in PAD4 and associated antixenotic effects. We hypothesize the significance of BIK-1 inhibition which could result in the improvement of the plant quality. We explain the interaction system in BIK-1 inhibition using mathematical model. Further, we adopted the plethora of computational modeling and simulations techniques to identify the mechanisms of molecular inhibition.

systems biology↗