Breast cancer (BC) is one of the main types of cancer that endangers women’s lives. The characteristics of triple-negative breast cancer (TNBC) include a high rate of recurrence and the capacity for metastasis; therefore, new therapies are urgently needed to combat TNBC. Dual targeting HDAC6 and Hsp90 has shown good synergistic effects in treating metastatic TNBC. The goal of this study was to find potential HDAC6 and Hsp90 dual inhibitors. Therefore, several in silico approaches have been used. An e-pharmacophore model generation based on the HDAC6-ligand complex and subsequently a pharmacophore-based virtual screening on 270,450 natural compounds from the ZINC were performed, which resulted in 12,663 compounds that corresponded to the obtained pharmacophoric hypothesis. These compounds were docked into HDAC6 and Hsp90. This resulted in the identification of three compounds with good docking scores and favorable free binding energy against the two targets. The top three compounds, namely ZINC000096116556, ZINC000020761262, and ZINC000217668954, were further subjected to ADME prediction and molecular dynamic simulations, which showed promising results in terms of pharmacokinetic properties and stability. As a result, these three compounds can be considered potential HDAC6 and Hsp90 dual inhibitors and are recommended for experimental evaluation.

Non-Hodgkin’s lymphomas are a diverse collection of lymphoproliferative cancers that are much less predictable than Hodgkin’s lymphomas with a far greater tendency to metastasize to extranodal sites. A quarter of non-Hodgkin’s lymphoma cases develop at extranodal sites and the majority of them involve nodal and extranodal sites. The most common subtypes include follicular lymphoma, chronic/small lymphocytic leukaemia, mantel cell lymphoma, and marginal zone lymphoma. Umbralisib is one of the latest PI3Kδ inhibitors in clinical trials for several hematologic cancer indications. In this study, new umbralisib analogues were designed and docked to the active site of PI3Kδ, the main target of the phosphoinositol-3-kinase/Akt/mammalian target of the rapamycin pathway (PI3K/AKT/mTOR). This study resulted in eleven candidates, with strong binding to PI3Kδ with a docking score between −7.66 and −8.42 Kcal/mol. The docking analysis of ligand–receptor interactions between umbralisib analogues bound to PI3K showed that their interactions were mainly controlled by hydrophobic interactions and, to a lesser extent, by hydrogen bonding. In addition, the MM-GBSA binding free energy was calculated. Analogue 306 showed the highest free energy of binding with −52.22 Kcal/mol. To identify the structural changes and the complexes’ stability of proposed ligands, molecular dynamic simulation was used. Based on this research finding, the best-designed analogue, analogue 306, formed a stable ligand–protein complex. In addition, pharmacokinetics and toxicity analysis using the QikProp tool demonstrated that analogue 306 had good absorption, distribution, metabolism, and excretion properties. Additionally, it has a promising predicted profile in immune toxicity, carcinogenicity, and cytotoxicity. In addition, analogue 306 had stable interactions with gold nanoparticles that have been studied using density functional theory calculations. The best interaction with gold was observed at the oxygen atom number 5 with −29.42 Kcal/mol. Further in vitro and in vivo investigations are recommended to be carried out to verify the anticancer activity of this analogue.

Plasmodium falciparum dihydrofolate reductase enzyme (P. falciparum DHFR) is one of the vital drug targets for malaria treatment, as this protein is indispensable for nucleotide metabolic pathways. This research aimed to discover promising phthalide derivatives against both wild and mutant P. falciparum DHFR enzymes through various computational techniques. The binding affinities were investigated using molecular docking, which showed five compounds having the highest affinity scores against both enzymes compared to the reference compounds. MM-GBSA calculations displayed favourable free binding energy. Moreover, the ADMET properties of the compounds are within acceptable ranges. The stability of the ligand-protein complexes was studied by Molecular Dynamics (MD) simulations. Depending on the results obtained from this research, we propose three compounds to be hit against P. falciparum DHFR activity which could be examined experimentally. Communicated by Ramaswamy Sarma

Cancer is considered one of the worldwide life-threatening and leading causes of human mortality. In 2020, 19,292,789 cancer cases and 9,958,133 cancer deaths have been estimated worldwide. Therefore, efforts have been devoted to discover novel anticancer agents. Bromodomains have a vital role in the regulation of transcription. Many reports have shown that bromodomain-containing protein 4 (BRD4) is an important target for cancer therapeutics. In this study, several in silico approaches were utilized to discover new inhibitors against the BRD4 protein using the Schrodinger suite. A library of 27 cytosporone E derivatives was docked into the active site of the BRD4 protein. Docked ligands showed docking scores ranging between −11.289 to −3.992 Kcal/mol. Ligands 1–4 showed better binding affinities with docking scores ranging from −11.289 to −8.917 Kcal/mol compared to the reference ligand BI-2536 (−8.426 Kcal/mol). These ligands displayed favorable MM-GBSA free binding energy. Also, ligands 1–4 were subjected to molecular dynamics simulations for 100 ns to get insight into the ligand-binding stability. These compounds exhibited an average RMSD below 2.8 Å, indicating the stability of the compounds with BRD4 protein. Further, Moreover, ligands 1–3 displayed favorable AMDET properties (absorption, distribution, metabolism, excretion, and toxicity). These new compounds might be potential leads to combat cancer. Communicated by Ramaswamy H. Sarma