Combining QSAR techniques, molecular docking, and molecular dynamics simulations to explore anti-tumor inhibitors targeting Focal Adhesion Kinase.

Focal Adhesion Kinase (FAK) is an important target for tumor therapy and is closely related to tumor cell genesis and progression. In this paper, we selected 46 FAK inhibitors with anticancer activity in the pyrrolo pyrimidine backbone to establish 3D/2D-QSAR models to explore the relationship between inhibitory activity and molecular structure. We have established two ideal models, namely, the Topomer CoMFA model (q2= 0.715, r2= 0.984) and the Holographic Quantitative Structure-Activity Relationship (HQSAR) model (q2= 0.707, r2= 0.899). Both models demonstrate excellent external prediction capabilities.Based on the QSAR results, we designed 20 structurally modified novel compounds, which were subjected to molecular docking and molecular dynamics studies, and the results showed that the new compounds formed many robust interactions with residues within the active pocket and could maintain stable binding to the receptor proteins. This study not only provides a powerful screening tool for designing novel FAK inhibitors, but also presents a series of novel FAK inhibitors with high micromolar activity that can be used for further characterization. It provides a reference for addressing the shortcomings of drug metabolism and drug resistance of traditional FAK inhibitors, as well as the development of novel clinically applicable FAK inhibitors.Communicated by Ramaswamy H. Sarma.

Discovery of novel BRD4-BD2 inhibitors via in silico approaches: QSAR techniques, molecular docking, and molecular dynamics simulations.

Bromodomain-containing protein 4(BRD4) plays an important role in the occurrence and development of various malignant tumors, which has attracted the attention of scientific research institutions and pharmaceutical companies. The structural modification of most currently available BRD4 inhibitors is relatively simple, but the drug effectiveness is limited. Research has found that the inhibition of BD1 may promote the differentiation of oligodendrocyte progenitor cell; however, the inhibition of BD2 will not cause this outcome. Therefore, newly potential drugs which target BRD4-BD2 need further research. Herein, we initially built QSAR models out of 49 compounds using HQSAR, CoMFA, CoMSIA, and Topomer CoMFA technology. All of the models have shown suitable reliabilities (q2 = 0.778, 0.533, 0.640, 0.702, respectively) and predictive abilities (r2pred = 0.716, 0.6289, 0.6153, 0.7968, respectively) for BRD4-BD2 inhibitors. On the basis of QSAR results and the search of the R-group in the topomer search module, we designed 20 new compounds with high activity that showed appropriate docking score and suitable ADMET. Docking studies and MD simulation were carried out to reveal the amino acid residues (Asn351, Cys347, Tyr350, Pro293, and Asp299) at the active site of BRD4-BD2. Free energy calculations and free energy landscapes verified the stable binding results and indicated stable conformations of the complexes. These theoretical studies provide guidance and theoretical basis for designing and developing novel BRD4-BD2 inhibitors.

Hypoxia inducible factor 1α promotes interleukin-1 receptor antagonist expression during hepatic ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion injury (IRI) is a major risk associated with liver surgery and transplantation, and its pathological mechanism is complex. Interleukin-1 receptor antagonist (IL-1ra) can protect the liver from IRI. However, the regulatory mechanism of IL-1ra expression is still unclear. AIM: To identify the mechanism that could protect the liver in the early stage of IRI. METHODS: To screen the key genes in hepatic IRI, we performed RNA sequencing and gene enrichment analysis on liver tissue from mice with hepatic IRI. Subsequently, we verified the expression and effect of IL-1ra in hepatic IRI. We also used promoter mutagenesis and chromatin immunoprecipitation assay to search for the transcriptional regulatory sites of hypoxia-inducible factor (HIF)-1α. Finally, to explore the protective mechanism of ischemic preconditioning (IP), we examined the expression of HIF-1α and IL-1ra after IP. RESULTS: We identified IL-1ra as a key regulator in hepatic IRI. The expression of IL-1ra was significantly upregulated after hepatic IRI both in vivo and in vitro. Furthermore, we found that HIF-1α regulated Il-1ra transcription in response to hypoxia. Increased HIF-1α accumulation promoted IL-1ra expression, whereas inhibition of HIF-1α exhibited the opposite effect. We also confirmed a predominant role for hypoxia response element in the regulation of Il1ra transcription by HIF-1α activation. Of note, we demonstrated that IP protects against hepatic IRI by inducing IL-1ra expression, which is mediated through HIF-1α. CONCLUSION: We demonstrated that ischemia or hypoxia leads to increased expression of IL-1ra through HIF-1α. Importantly, IP protects the liver from IRI via the HIF-1α-IL-1ra pathway.

Computational strategies towards developing novel SARS-CoV-2 Mpro inhibitors against COVID-19.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains to be a serious threat due to the lack of a specific therapeutic agent. Computational methods are particularly suitable for rapidly fight against SARS-CoV-2. This present research aims to systematically explore the interaction mechanism of a series of novel bicycloproline-containing SARS-CoV-2 Mpro inhibitors through integrated computational approaches. We designed six structurally modified novel SARS-CoV-2 Mpro inhibitors based on the QSAR study. The four designed compounds with higher docking scores were further explored through molecular docking, molecular dynamics (MD) simulations, free energy calculations, and residual energy contributions estimated by the MM-PBSA approach, with comparison to compound 23(PDB entry 7D3I). This research not only provides robust QSAR models as valuable screening tools for the development of anti-COVID-19 drugs, but also proposes the newly designed SARS-CoV-2 Mpro inhibitors with nanomolar activities that can be potentially used for further characterization to treat SARS-CoV-2 virus.