Microfluidic-Assisted Preparation of Targeted pH-Responsive Polymeric Micelles Improves Gemcitabine Effectiveness in PDAC: In Vitro Insights

Pancreatic ductal adenocarcinoma (PDAC) represents a great challenge to the successful delivery of the anticancer drugs. The intrinsic characteristics of the PDAC microenvironment and drugs resistance make it suitable for therapeutic approaches with stimulus-responsive drug delivery systems (DDSs), such as pH, within the tumor microenvironment (TME). Moreover, the high expression of uPAR in PDAC can be exploited for a drug receptor-mediated active targeting strategy. Here, a pH-responsive and uPAR-targeted Gemcitabine (Gem) DDS, consisting of polymeric micelles (Gem@TpHResMic), was formulated by microfluidic technique to obtain a preparation characterized by a narrow size distribution, good colloidal stability, and high drug-encapsulation efficiency (EE%). The Gem@TpHResMic was able to perform a controlled Gem release in an acidic environment and to selectively target uPAR-expressing tumor cells. The Gem@TpHResMic displayed relevant cellular internalization and greater antitumor properties than free Gem in 2D and 3D models of pancreatic cancer, by generating massive damage to DNA, in terms of H2AX phosphorylation and apoptosis induction. Further investigation into the physiological model of PDAC, obtained by a co-culture of tumor spheroids and cancer-associated fibroblast (CAF), highlighted that the micellar system enhanced the antitumor potential of Gem, and was demonstrated to overcome the TME-dependent drug resistance. In vivo investigation is warranted to consider this new DDS as a new approach to overcome drug resistance in PDAC.

Big Data Approach to Large Scale Molecular Dynamics Simulations: Necessity and Inevitability for Drug Design

Molecular Dynamics (MD) simulations model motion of molecules in atomistic detail and aid in drug design. While simulations on large systems may require several days to complete, analysis of terabytes of data generated in the process could also be time consuming. Recent studies captured exciting and dramatic drug-receptor interactions under cell-like complex conditions. Such advances make simulations of biomolecular interactions more realistic, insightful, and informative and have potential to make drug design more realistic. However, currently available resources and techniques do not provide, in reasonable time, a comprehensive understanding of events seen in simulations. We demonstrate that big data approach results in significant speedups, and provides rapid insights into simulations performed. Advancing this improvement, we propose a scalable, self-tuning, and responsive framework based on Cloud-infrastructure to accomplish the best possible MD studies with given priorities and within available resources.

Chemopreventive potential of linalool in targeting lung cancer biomarkers: An in silico & in vitro investigation

Background: Phytochemicals are used to treat lung cancer in contemporary and traditional medicine. The limitations of known chemotherapeutic drugs such as non-specificity, resistance, and toxicity restrict their use for lung cancer treatment. Therefore, the search for target-specific novel entities is required continuously. Objective: Linalool, a monoterpene alcohol that possesses antiviral, anti-inflammatory, and antibacterial properties, is present in sweet basil, laurel, jasmine, rosewood and lavender. Previous reports revealed its anticancer potential against colon, breast and liver cancer. In this study, linalool's efficacy in targeting biomarkers associated with different lung cancer stages has been investigated Methods: The insilico molecular docking analysis was used to explore drug receptor interaction, and further, linalools cytotoxicity potential was evaluated on lung adenocarcinoma cell line (A549). The toxicity profiling of linalool was done by ADMET analysis. Results: In results Linalool revealed an excellent binding affinity with the selected targets. It showed the highest interaction with BRAF with binding energy -5.6 kcal/mol. Furthermore, it successfully interacts within the binding pocket of BRAF, similar to its inhibitor (Sorafenib). In MTT analysis, linalool significantly reduces the percent viability (IC30 474.94 ± 43.12, 379.33 ± 49.5, and 183.77 ± 66.7 µM in A549 cell lines for 24, 48, and 72 h respectively. Conclusion: These results concluded that linalool possesses chemopreventive potential against lung cancer by interacting or modulating selected biomarkers associated with a lung cancer diagnosis, progression, and proliferation.

Exploring the Monoterpene Indole Alkaloid Scaffold for Reversing P-Glycoprotein-Mediated Multidrug Resistance in Cancer

Dregamine (1), a major monoterpene indole alkaloid isolated from Tabernaemontana elegans, was submitted to chemical transformation of the ketone function, yielding 19 azines (3–21) and 11 semicarbazones (22–32) bearing aliphatic or aromatic substituents. Their structures were assigned mainly by 1D and 2D NMR (COSY, HMQC, and HMBC) experiments. Compounds 3–32 were evaluated as multidrug resistance (MDR) reversers through functional and chemosensitivity assays in a human ABCB1-transfected mouse T-lymphoma cell model, overexpressing P-glycoprotein. A significant increase of P-gp inhibitory activity was observed for most derivatives, mainly those containing azine moieties with aromatic substituents. Compounds with trimethoxyphenyl (17) or naphthyl motifs (18, 19) were among the most active, exhibiting strong inhibition at 0.2 µM. Moreover, most of the derivatives showed selective antiproliferative effects toward resistant cells, having a collateral sensitivity effect. In drug combination assays, all compounds showed to interact synergistically with doxorubicin. Selected compounds (12, 17, 18, 20, and 29) were evaluated in the ATPase activity assay, in which all compounds but 12 behaved as inhibitors. To gather further insights on drug–receptor interactions, in silico studies were also addressed. A QSAR model allowed us to deduce that compounds bearing bulky and lipophilic substituents were stronger P-gp inhibitors.

Iodine -A Versatile reagent for Vinylogous Mannich Reaction for the Synthesis of δ-Amino γ-Butenolides and Insilico Evaluation

A set of δ-amino γ-butenolides (1-5) were synthesised by a novel method using molecular iodine as a catalyst by mannich reaction. The purity and progress of the reaction was assessed by thin layer chromatography and the compounds characterisation was done by IR, proton NMR and mass spectroscopic techniques. Molecular modeling studies for the compounds such as docking was performed for the synthesized butenolides to understand the drug receptor interactions and analyze structural changes when bound to the active site of the receptor. the results showed that the compounds 2 and 3 showed significant interaction with target enzymes.

Potent phytochemicals against COVID-19 infection from phyto-materials used as antivirals in complementary medicines: a review

Background Following the outbreak of the COVID-19 pandemic, there was a surge of research activity to find methods/drugs to treat it. There has been drug-repurposing research focusing on traditional medicines. Concomitantly, many researchers tried to find in silico evidence for traditional medicines. There is a great increase in article publication to commensurate the new-found research interests. This situation inspired the authors to have a comprehensive understanding of the multitude of publications related to the COVID-19 pandemic with a wish to get promising drug leads. Main body This review article has been conceived and made as a hybrid of the review of the selected papers advertised recently and produced in the interest of the COVID-19 situation, and in silico work done by the authors. The outcome of the present review underscores a recommendation for thorough MDS analyses of the promising drug leads. The inclusion of in silico work as an addition to the review was motivated by a recently published article of Toelzer and colleagues. The in silico investigation of free fatty acids is novel to the field and it buttresses the further MDS analysis of drug leads for managing the COVID-19 pandemic. Conclusion The review performed threw light on the need for MDS analyses to be considered together with the application of other in silico methods of prediction of pharmacologic properties directing towards the sites of drug-receptor regulation. Also, the present analysis would help formulate new recipes for complementary medicines.

Integrated Role of Nanotechnology and Pharmacogenetics in Diagnosis and Treatment of Diseases

“One size fits all” is an erroneous paradigm in drug delivery, due to side effects/adverse effects and variability observed in drug response. The variability is a result of geneotypic variations (variability in genomic constitution) which is studied in the branch of science called Pharmacogenomics. The variability in drug response is studied by multigene analysis or profiling of whole-genome single nucleotide polymorphism (SNP) and is recorded in terms of the pharmacokinetic (absorption, distribution, metabolism and elimination) and pharmacodynamic (drug-receptor interaction, immune response, etc.) response of the drug. Therefore, a foray into this research area can provide valuable information for designing of drug therapies, identifying disease etiology, therapeutic targets and biomarkers for application in treatment and diagnosis of diseases. Lately, with the integration of pharmacogenomics and nanotechnology, a new facade for the diagnosis and treatment of diseases has opened up, and the prescription pattern of drugs has moved to pharmacotyping (individualized dose and dosage-form adjusted therapy) using nanoplatforms like nanobioconjugates, nanotheranostics, etc.