Antiangiogenic potential of phytochemicals from Clerodendrum inerme (L.) Gaertn investigated through in silico and quantum computational methods.

Suppressing vascular endothelial growth factor (VEGF), its receptor (VEGFR2), and the VEGF/VEGFR2 signaling cascade system to inhibit angiogenesis has emerged as a possible cancer therapeutic target. The present work was designed to discover and evaluate bioactive phytochemicals from the Clerodendrum inerme (L.) Gaertn plant for their anti-angiogenic potential. Molecular docking of twenty-one phytochemicals against the VEGFR-2 (PDB ID: 3VHE) protein was performed, followed by ADMET profiling and molecular docking simulations. These investigations unveiled two hit compounds, cirsimaritin (- 12.29 kcal/mol) and salvigenin (- 12.14 kcal/mol), with the highest binding energy values when compared to the reference drug, Sorafenib (- 15.14 kcal/mol). Furthermore, only nine phytochemicals (cirsimaritin and salvigenin included) obeyed Lipinski's rule of five and passed ADMET filters. Molecular dynamics simulations run over 100 ns revealed that the protein-ligand complexes remained stable with minimal backbone fluctuations. The binding free energy values of cirsimaritin (- 52.35 kcal/mol) and salvigenin (- 55.89 kcal/mol), deciphered by MM-GBSA analyses, further corroborated the docking interactions. The HOMO-LUMO band energy gap (ΔE) was calculated using density-functional theory (DFT) and substantiated using density of state (DOS) spectra. The chemical reactivity analyses revealed that salvigenin exhibited the highest chemical softness value (6.384 eV), the lowest hardness value (0.07831 eV), and the lowest ΔE value (0.1566 eV), which implies salvigenin was less stable and chemically more reactive than cirsimaritin and sorafenib. These findings provide further evidence that cirsimaritin and salvigenin have the ability to prevent angiogenesis and the development of cancer. Nevertheless, more in vitro and in vivo confirmation is necessary.

Screening of phytochemicals from Clerodendrum inerme (L.) Gaertn as potential anti-breast cancer compounds targeting EGFR: an in-silico approach.

Breast cancer (BC) is the most prevalent malignancy among women around the world. The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor (RTK) of the ErbB/HER family. It is essential for triggering the cellular signaling cascades that control cell growth and survival. However, perturbations in EGFR signaling lead to cancer development and progression. Hence, EGFR is regarded as a prominent therapeutic target for breast cancer. Therefore, in the current investigation, EGFR was targeted with phytochemicals from Clerodendrum inerme (L.) Gaertn (C. inerme). A total of 121 phytochemicals identified by gas chromatography-mass spectrometry (GC-MS) analysis were screened against EGFR through molecular docking, ADMET analyses (Absorption, Distribution, Metabolism, Excretion, and Toxicity), PASS predictions, and molecular dynamics simulation, which revealed three potential hit compounds with CIDs 10586 [i.e. alpha-bisabolol (-6.4 kcal/mol)], 550281 [i.e. 2,(4,4-Trimethyl-3-hydroxymethyl-5a-(3-methyl-but-2-enyl)-cyclohexene) (-6.5 kcal/mol)], and 161271 [i.e. salvigenin (-7.4 kcal/mol)]. The FDA-approved drug gefitinib was used to compare the inhibitory effects of the phytochemicals. The top selected compounds exhibited good ADMET properties and obeyed Lipinski's rule of five (ROF). The molecular docking analysis showed that salvigenin was the best among the three compounds and formed bonds with the key residue Met 793. Furthermore, the molecular mechanics generalized born surface area (MMGBSA) calculations, molecular dynamics simulation, and normal mode analysis validated the binding affinity of the compounds and also revealed the strong stability and compactness of phytochemicals at the docked site. Additionally, DFT and DOS analyses were done to study the reactivity of the compounds and to further validate the selected phytochemicals. These results suggest that the identified phytochemicals possess high inhibitory potential against the target EGFR and can treat breast cancer. However, further in vitro and in vivo investigations are warranted towards the development of these constituents into novel anti-cancer drugs.Communicated by Ramaswamy H. Sarma.

Possibility of averting cytokine storm in SARS-COV 2 patients using specialized pro-resolving lipid mediators.

Fatal "cytokine storms (CS)" observed in critically ill COVID-19 patients are consequences of dysregulated host immune system and over-exuberant inflammatory response. Acute respiratory distress syndrome (ARDS), multi-system organ failure, and eventual death are distinctive symptoms, attributed to higher morbidity and mortality rates among these patients. Consequent efforts to save critical COVID-19 patients via the usage of several novel therapeutic options are put in force. Strategically, drugs being used in such patients are dexamethasone, remdesivir, hydroxychloroquine, etc. along with the approved vaccines. Moreover, it is certain that activation of the resolution process is important for the prevention of chronic diseases. Until recently Inflammation resolution was considered a passive process, rather it's an active biochemical process that can be achieved by the use of specialized pro-resolving mediators (SPMs). These endogenous mediators are an array of atypical lipid metabolites that include Resolvins, lipoxins, maresins, protectins, considered as immunoresolvents, but their role in COVID-19 is ambiguous. Recent evidence from studies such as the randomized clinical trial, in which omega 3 fatty acid was used as supplement to resolve inflammation in COVID-19, suggests that direct supplementation of SPMs or the use of synthetic SPM mimetics (which are still being explored) could enhance the process of resolution by regulating the aberrant inflammatory process and can be useful in pain relief and tissue remodeling. Here we discussed the biosynthesis of SPMs, & their mechanistic pathways contributing to inflammation resolution along with sequence of events leading to CS in COVID-19, with a focus on therapeutic potential of SPMs.

Antibiotic adjuvants: synergistic tool to combat multi-drug resistant pathogens.

The rise of multi-drug resistant (MDR) pathogens poses a significant challenge to the field of infectious disease treatment. To overcome this problem, novel strategies are being explored to enhance the effectiveness of antibiotics. Antibiotic adjuvants have emerged as a promising approach to combat MDR pathogens by acting synergistically with antibiotics. This review focuses on the role of antibiotic adjuvants as a synergistic tool in the fight against MDR pathogens. Adjuvants refer to compounds or agents that enhance the activity of antibiotics, either by potentiating their effects or by targeting the mechanisms of antibiotic resistance. The utilization of antibiotic adjuvants offers several advantages. Firstly, they can restore the effectiveness of existing antibiotics against resistant strains. Adjuvants can inhibit the mechanisms that confer resistance, making the pathogens susceptible to the action of antibiotics. Secondly, adjuvants can enhance the activity of antibiotics by improving their penetration into bacterial cells, increasing their stability, or inhibiting efflux pumps that expel antibiotics from bacterial cells. Various types of antibiotic adjuvants have been investigated, including efflux pump inhibitors, resistance-modifying agents, and compounds that disrupt bacterial biofilms. These adjuvants can act synergistically with antibiotics, resulting in increased antibacterial activity and overcoming resistance mechanisms. In conclusion, antibiotic adjuvants have the potential to revolutionize the treatment of MDR pathogens. By enhancing the efficacy of antibiotics, adjuvants offer a promising strategy to combat the growing threat of antibiotic resistance. Further research and development in this field are crucial to harness the full potential of antibiotic adjuvants and bring them closer to clinical application.