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Proteolysis targeting chimeras (PROTACs) have proven to be a novel approach for the degradation of disease-causing proteins in drug discovery. One of the E3 ligases for which efficient PROTACs have been described is the Von Hippel-Lindau factor (VHL). However, the development of PROTACs has so far often relied on a minimum of computational tools, so that it is mostly based on a trial-and-error process. Therefore, there is a great need for resource- and time-efficient structure-based or computational approaches to streamline PROTAC design. In this study, we present a combined computational approach that integrates static ternary complex formation, induced-fit docking, and molecular dynamics (MD) simulations. Our methodology was tested using four experimentally derived ternary complex structures of VHL PROTACs, reported for BRD4, SMARCA2, FAK, and WEE1. In addition, we applied the validated approach to model a recently in-house developed FLT3-targeted PROTAC (MA49). The results show that static ternary models generated with a protein–protein docking method implemented in the software MOE have a high predictive power for reproducing the experimental 3D structures. The induced-fit docking of different active PROTACs to their respective models showed the reliability of this model for the development of new VHL-mediated degraders. In particular, the induced-fit docking was sensitive to structural changes in the PROTACs, as evidenced by the failed binding modes of the PROTAC negative controls. Furthermore, MD simulations confirmed the stability of the generated complexes and emphasized the importance of dynamic studies for understanding the relationship between PROTAC structure and function.

Tacrolimus (Tac) is an immunosuppressive drug used to reduce the risk of allograft rejection; however, it can induce renal injury. High mobility group box 1 (HMGB-1) protein, which induces inflammation through the aberrant stimulation of the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response protein (MyD88)/nuclear factor kappa B (NF-κB) trajectory, could represent a molecular target for alleviating Tac-induced renal damage. The present study aimed to investigate the potential protective role of the GLP-1 agonist, dulaglutide (Dula), against Tac-induced nephrotoxicity in rats. Rats were administered Tac (5 mg/kg/day) and vehicle or Dula (0.2 mg/kg once a week) for 14 days. Treatment with Dula reduced serum creatinine plus blood urea nitrogen and attenuated Tac-induced renal histopathological changes. Dula treatment also hampered renal inflammation and restored redox homeostasis, as indicated by remarkably reduced tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), malondialdehyde (MDA), and NADPH oxidase 1 levels alongside marked replenishment in reduced glutathione (GSH) content. These effects were mediated through the upregulation of miR-22 expression and the consequent inhibition of the HMGB-1/TLR4/MyD88/NF-κB trajectory. Collectively, Dula has been demonstrated to protect rats against Tac-induced nephrotoxicity by reducing inflammation, restoring redox homeostasis, and modulation of the miR-22/HMGB-1/TLR4/MyD88/NF-κB trajectory. Dula may be beneficial clinically in preventing Tac-induced renal injury.

The epidermal growth factor receptor (EGFR) family, comprising receptor tyrosine kinases (RTK) such as EGFR and HER2, plays a critical role in various signaling pathways related to cell proliferation, differentiation, and growth. EGFR overactivation due to aberrant signaling can lead to various cancers, including non-small cell lung cancer (NSCLC). To develop treatment for EGFR-related NSCLC, several tyrosine kinase inhibitors (TKIs) were designed: gefitinib, erlotinib, as first-generation; neratinib, dacomitinib as second-generation; osimertinib, lazertinib as third-generation, as examples. However, due to the acquired resistance by the mutations such as EGFR^T790M and EGFR^C797S together with the exon 20 insertion mutations, these drugs do not provide promising results for NSCLC patients. The development of fourth-generation inhibitors like EAI045 and further innovative drugs to overcome this resistance problem is a must to cure EGFR-related NSCLC. Among these, pyrazoline-thiazole scaffolds are found effective as EGFR-HER2 inhibitors against NSCLC, making them promising drug candidates. Although structures obtained so far for the EGFR family provide meaningful insights into the mechanisms, the quality and the quantity of the EGFR family structures are insufficient to elucidate the complete structures and functions to overcome NSCLC. This review evaluates the structures of EGFR-HER2 and investigates their relation to NSCLC.

Type V MAPK inhibitors are distinguished by their capacity to target both the ATP binding site and a specific allosteric site on the enzyme. The present work utilized in silico analysis with Maestro 13.8.135 (Schrodinger) software in conjunction with experimental investigations to enhance the antiproliferative efficacy and forecast the likely mechanism of action of benzothiazole derivatives. Approximately 28 compounds were developed, produced, and assessed for their antiproliferative properties against two breast cancer cell lines: ER+ (MCF7) and ER- (MDA-MB-231), in addition to one normal mouse fibroblast cell line (L929). Their antiproliferative activities were evaluated via the MTT test, with doxorubicin and cisplatin serving as reference drugs for comparison. Consequently, the compounds with the greatest activity against the MCF7 cell line were chosen, and their inhibitory effects on the p38α MAPK enzyme were examined. The molecular docking studies of compounds 15 and 19 demonstrated significant binding affinities for p38α MAPK. Molecular dynamics simulations conducted over 100 ns revealed that compounds 15 and 19 exhibit stability inside both the ATP-binding domain and the lipid domain of p38α MAPK. The research focused on creating effective Type V MAPK inhibitors demonstrate that compounds 15 and 19 possess considerable ability to inhibit p38α MAPK, hence establishing them as promising anticancer agents.

This study aimed at generating preliminary evidence for the potential utility of repurposing the clinically approved anti-ischemic drug trimetazidine (TMZ) against methotrexate (MTX)-induced hepatotoxicity. In this study, rats received MTX (30 mg/kg) with or without TMZ pretreatment (20 mg/kg). MTX caused a 2.7–3.6-fold increase in serum transaminases, while TMZ pretreatment caused a 37%–40% reduction. Regarding oxidative markers, MTX significantly suppressed the antioxidant glutathione (GSH) levels by 37% and elevated malondialdehyde (MDA) levels by 29%, while TMZ boosted GSH levels by 40% and reduced MDA levels by 20%. Next, we assessed nuclear factor kappa B (NF-κB) (p-65), nuclear factor erythroid 2-related factor 2 (Nrf2) and hemoxygenase-1 (HO-1) to find that MTX significantly elevated the levels of the proinflammatory nuclear factor kappa B (NF-κB) (p65) by 2.4-fold, while TMZ pretreatment reduced its levels by 48%. Conversely, MTX decreased the levels of Nrf2, HO-1, and adenosine triphosphate (ATP) by 55%–71%, while TMZ led to a threefold increase in their levels. Regarding apoptosis, MTX caused a five to sixfold elevation in B-cell lymphoma 2 associated X (Bax)/B-cell lymphoma 2 (BCL2) ratio and caspase-3, while TMZ pretreatment caused a threefold reduction in their levels. An in silico analysis of TMZ protein target-prediction revealed statistically enriched pathways related to oxidative stress, inflammation, and apoptosis. In conclusion, pretreatment with TMZ successfully ameliorated MTX-induced alterations in serum aminotransferases, liver histology, oxidative stress, and apoptosis. Pathway enrichment analysis (PEA) showed that TMZ is involved in multiple signaling and immune-related pathways that might be, at least partly, implicated in its cytoprotective effects.

A large set of hydrazide-based derivatives were explored as inhibitors of the human (h) carbonic anhydrase (CA) isoforms I, II, IV, IX, and XII. A wide series of compounds were synthesized and then assessed for their CA inhibitory activity using a CO₂ hydrase stopped-flow assay. Generally, these inhibitors demonstrated micromolar activity against the evaluated hCAs. Specifically, some derivatives bearing a ureido-linker exhibited the highest inhibitory potency, showing inhibition constants (K_Is) in the low-micromolar range against hCAs IV, XI, and XII. Moreover, two of them were detected as submicromolar inhibitors of isoform IV (K_Is: 0.8–0.96 µM). Molecular modeling was carried out to investigate the binding mode of the most selective and potent compounds and reinforce the experimental results. The latter suggests that hydrazide compounds act as zinc binders, being bidentate ligands, and can be developed as an alternative to classic CA inhibitors.