An integrated computational approach of molecular dynamics simulations, receptor binding studies and pharmacophore mapping analysis in search of potent inhibitors against tuberculosis

Tuberculosis is an infectious chronic disease caused by obligate pathogen Mycobacterium tuberculosis that affects millions of people worldwide. Although many first and second line drugs are available for its treatment, but their irrational use has adversely lead to the emerging cases of multiple drug resistant and extensively drug-resistant tuberculosis. Therefore, there is an intense need to develop novel potent analogues for its treatment. This has prompted us to develop potent analogues against TB. The Mycobacterium tuberculosis genome provides us with number of validated targets to combat against TB. Study of Mtb genome disclosed six epoxide hydrolases (A to F) which convert harmful epoxide into diols and act as a potential drug target for rational drug design. Our current strategy is to develop such analogues which inhibits epoxide hydrolase enzyme present in Mtb genome. To achieve this, we adopted an integrated computational approach involving QSAR, pharmacophore mapping, molecular docking and molecular dynamics simulation studies. The approach envisaged vital information about the role of molecular descriptors, essential pharmacophoric features and binding energy for compounds to bind into the active site of epoxide hydrolase. Molecular docking analysis revealed that analogues exhibited significant binding to Mtb epoxide hydrolase. Further, three docked complexes 2s, 37s and 15s with high, moderate and low docking scores respectively were selected for molecular dynamics simulation studies. RMSD analysis revealed that all complexes are stable with average RMSD below 2 Å throughout the 10 ns simulations. The B-factor analysis showed that the active site residues of epoxide hydrolase are flexible enough to interact with inhibitor. Moreover, to confirm the binding of these urea derivatives, MM-GBSA binding energy analysis were performed. The calculations showed that 37s has more binding affinity (ΔGtotal = −52.24 kcal/mol) towards epoxide hydrolase compared to 2s (ΔGtotal = −51.70 kcal/mol) and 15s (ΔGtotal = −49.97 kcal/mol). The structural features inferred in our study may provide the future directions to the scientists towards the discovery of new chemical entity exhibiting anti-TB property.AICTE and Department of Science and Technology, New Delhi.http://www.elsevier.com/locate/JMGM2019-08-01hj2018Plant Production and Soil Scienc

Herbal nanogels: Revolutionizing skin cancer therapy through nanotechnology and natural remedies

The escalating global incidence of skin cancer demands innovative therapeutic approaches that balance efficacy and reduced side effects. The convergence of nanotechnology and medicinal research has unveiled herbal nanogels as promising candidates for advancing skin cancer therapy. Skin cancer, comprising diverse malignancies, necessitates novel strategies to enhance treatment outcomes. Nanogels, intricate networks of cross-linked polymers at the nanoscale, have emerged as versatile vehicles for targeted drug delivery. Their ability to encapsulate a range of therapeutic agents and respond to stimuli offers a platform to revolutionize treatment paradigms. The taxonomy of nanogels encompasses physical cross-linked gels, liposome-modified nanogels, micellar nanogels, hybrid nanogels, and chemically cross-linked nanogels, each holding distinctive characteristics suitable for specific applications. The synthesis of nanogels is a precise craft involving techniques like photolithography, micro-moulding, and emulsion methods, enabling control over particle size, morphology, and drug-loading capacity. Stimuli-responsive nanogels present a dynamic facet of this field, exhibiting potential for targeted drug delivery. Noteworthy examples include LHRH-targeted nanogels and nanogels responsive to the intricate microenvironment of bacterial-accumulated tumors. One of the most intriguing developments lies in the fusion of herbal medicine and nanotechnology, paving the way for herbal nanogels. By incorporating bioactive plant-derived compounds into nanogel matrices, these constructs offer a holistic therapeutic approach. The convergence of nanotechnology and herbal medicine in the form of herbal nanogels presents a promising avenue for elevating skin cancer therapy. Through precise drug delivery mechanisms and responsiveness to complex microenvironments, nanogels exhibit a potential to reshape treatment norms. This comprehensive review provides an in-depth roadmap of the evolving landscape of herbal nanogels, illuminating their potential as effective, targeted, and minimally invasive tools for combating skin cancer

siRNA Delivery Strategies: A Comprehensive Review of Recent Developments

siRNA is a promising therapeutic solution to address gene overexpression or mutations as a post-transcriptional gene regulation process for several pathological conditions such as viral infections, cancer, genetic disorders, and autoimmune disorders like arthritis. This therapeutic method is currently being actively pursued in cancer therapy because siRNA has been found to suppress the oncogenes and address mutations in tumor suppressor genes and elucidate the key molecules in cellular pathways in cancer. It is also effective in personalized gene therapy for several diseases due to its specificity, adaptability, and broad targeting capability. However, naked siRNA is unstable in the bloodstream and cannot efficiently cross cell membranes besides being immunogenic. Therefore, careful design of the delivery systems is essential to fully utilize the potential of this therapeutic solution. This review presents a comprehensive update on the challenges of siRNA delivery and the current strategies used to develop nanoparticulate delivery systems

QSAR analysis of furanone derivatives as potential COX-2 inhibitors: kNN MFA approach

A series of thirty-two furanone derivatives with their cyclooxygenase-2 inhibitory activity were subjected to quantitative structural–activity relationship analysis to derive a correlation between biological activity as a dependent variable and various descriptors as independent variables by using V-LIFE MDS3.5 software. The significant 2D QSAR model showed correlation coefficient (r2) = 0.840, standard error of estimation (SEE) = 0.195, and a cross-validated squared correlation coefficient (q2) = 0.773. The descriptors involved in the building of 2D QSAR model are retention index for six membered rings, total number of oxygen connected with two single bonds, polar surface area excluding P and S plays a significant role in COX-2 inhibition. 3D-QSAR performed via Step Wise K Nearest Neighbor Molecular Field Analysis [(SW) kNN MFA] with partial least-square (PLS) technique showed high predictive ability (r2 = 0.7622, q2 = 0.7031 and standard error = 0.3660) explaining the majority of the variance in the data with two principle components. The results of the present study may be useful in the design of more potent furanone derivatives as COX-2 inhibitors