Background & objective: Molecular dynamics simulations (MDS) using GROMACS are among the commonly used computational experiments in the area of molecular biology and drug discovery. This article pr... Graphical abstract

The Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation is one of the most prevailing mutations in various tumors and is difficult to cure. Long-term proliferation in carcinogenesis is primarily initiated by oncogenic KRAS-downstream signaling. Recent research suggests that it also activates the autocrine effect and interplays the tumor microenvironment (TME). Here, we discuss the emerging research, including KRAS mutations to immune evasion in TME, which induce immunological modulation that promotes tumor development. This review gives an overview of the existing knowledge of the underlying connection between KRAS mutations and tumor immune modulation. It also addresses the mechanisms to reduce the effect of oncogenes on the immune system and recent advances in clinical trials for immunotherapy in KRAS-mutated cancers.

Macrophage mannose receptor (MMR) is a C-type lectin that regulates the phagocytosis and phagocytosis-lysosome (P-L) fusion in tuberculosis. Mannose-capped lipoarabinomannan (ManLAM), a lipoglycan present at the surface of Mycobacterium tuberculosis (MT), is an important factor in phagocyte attachment and internalization that is specific for MMR. Based on this idea, herein we have designed our experiment to understand the better site-specific delivery against tuberculosis. An experimental outcome was used as a basis to revisit the reverse experimental strategy for tuberculosis management. Stearic mannose was prepared from stearic acid incubation with the D-mannose. Interestingly, stearic mannose explained its internalisation via stimulating actin-mediated phagocytic pathway of MMR experimentally. Following, an in silico strategy towards hypothetical designing of various mannose-stearyl conjugates (SBKK1-7) against tuberculosis, as binding promoter of MMR (PDB: 1EGI), was carried out using molecular docking and dynamics approaches. Overall, SPKK-5 viz. ortho stearic mannose (OSM) showed a higher binding affinity with notable H-bonding and hydrophobic interactions. Pharmacokinetic and toxicity examinations illustrated an ideal range of descriptors values for apex screened compounds. Molecular dynamics simulations have confirmed its significant intactness with the MMR. Ultimately, the whole effort led to the identification of promising hit (SBKK-5), which positively correlates with the experimental work and furthermore need to explore its novel drug delivery systems with improved anti-tubercular therapy.

Cancer has remained a major global health challenge, with around 20 million new cases and 9.7 million fatalities recorded each year. Even though there has been recent progress in therapies such as radiotherapy, chemotherapy, immunotherapy, and gene therapy, cancer remains a major treatment challenge due to late diagnosis and difficulties in therapeutic effectiveness. Flavonoids, a substantial category of naturally occurring polyphenols, have received considerable interest in recent years for their potential involvement in cancer management and prevention, especially concerning breast cancer. These bioactive compounds, abundant in vegetables, fruits, and herbs, exhibit various therapeutic actions, including antioxidant, anti-inflammatory, and antimutagenic effects. The advanced therapeutic potential of flavonoids, when combined with FDA-approved medicines, offers synergistic effects and enhanced clinical results. Additionally, flavonoid-loaded nano-formulations, involving co-delivery systems, are being explored to increase solubility, stability, and bioavailability, enabling targeted delivery to cancer cells while reducing off-target adverse effects. This review examines the role of flavonoids in the prevention and management of breast cancer, focusing on their dietary sources, metabolism, and pharmacokinetic properties. Furthermore, we explore novel strategies, such as combination therapies with FDA-approved drugs and the application of flavonoid-based nanoformulations, which have the potential to enhance therapeutic outcomes. The clinical application of these strategies has the potential to improve breast cancer treatment and create new opportunities for the advancement of flavonoid-based therapies.

Emerging cases of drug resistance against Artemisinin combination therapies which are the current and the last line of defense against malaria makes the situation very alarming. Due to the liability of single-target drugs to be more prone to drug resistance, the trend of development of dual or multi-target inhibitors is emerging. Recently, a malaria box molecule, MMV007571 which is a well known new permeability pathways inhibitor was investigated to be also multi-targeting Plasmodium falciparum dihydroorotate dehydrogenase and cytochrome bc1 complex. The aspiration behind this study was to use the information of its pharmacophoric features essential for binding as two of its new targets. In this regard, high throughput virtual screening involving pharmacophore mapping, ADME filtering, molecular docking, and MM-GBSA calculations were carried out. This approach has lead to the identification of two new hits namely DT00V1902 and DT00V1922 which binds with -37.85 and -24.65 kcal/mol of more stable ΔG Bind energy at two targets than the lead molecule, MMV007571. The screened compounds are indicated to be carry improvement in binding potential and pharmacokinetic characters as per in silico studies. The authors propose that DT00V1902 and DT00V1922 can be forwarded for experimental validation and clinical studies for antimalarial chemotherapy. Communicated by Ramaswamy H. Sarma