Coumarins, dihydroisocoumarins, a dibenzo-α-pyrone, a meroterpenoid, and a merodrimane from Talaromyces amestolkiae.

Chemical investigation of an organic extract of a fungus isolated from submerged wood collected from fresh water (strain G173), identified as a Talaromyces amestolkiae (Eurotiales; Trichocomaceae), led to the isolation of three coumarins, three dihydroisocoumarins, a dibenzo-α-pyrone, a meroterpenoid, and a merodrimane. Three of the isolated compounds, namely 7-chloropestalasin A (3), 4-hydroxyaspergillumarin (6), and ent-thailandolide B (9) were new. The structures were elucidated using a combination of spectroscopic and spectrometric techniques. The absolute configurations of 2, 3, 5, and 6 were established via a modified Mosher's ester method, whereas for 9 a combination of TDDFT ECD and ORD calculations were employed. Compounds 1-9 were evaluated for antimicrobial activity against a group of bacteria and fungi.

Hit identification of SMYD3 enzyme inhibitors using structure-based pharmacophore modeling.

Aim: SMYD3 enzyme is overexpressed in many types of cancer and its role in the methylation of cytoplasmic mitogen-activated protein kinase, kinase kinase 2 (MAP3K2), has been linked to promotion of Kras-driven cancer in pancreatic ductal and lung adenocarcinoma. Materials & methods: A hybrid 3D structure-based pharmacophore model was generated using crystal structures of SMYD3 complexed with sinefungin and was used to search for potential SMYD3 inhibitors through virtual screening of the Maybridge database. The retrieved hits from screening were further docked into the binding site of SMYD3 using CDOCKER docking algorithms. The top-ranked hits were selected and their inhibitory activity was evaluated. Results & conclusion: The results obtained helped us to find an SMYD3 small molecule hit inhibitor scaffold.

Explaining the autoinhibition of the SMYD enzyme family: A theoretical study.

The SMYD enzymes (SMYD1-5) are lysine methyltransferases that have diverse biological functions including gene expression and regulation of skeletal and cardiac muscle development and function. Recently, they have gained more attention as potential drug targets because of their involvement in cardiovascular diseases and in the progression of different cancer types. Their activity has been suggested to be regulated by a posttranslational mechanism and by autoinhibition. The later relies on a hinge-like movement of the N- and C-lobes to adopt an open or closed conformation, consequently, determining the accessibility of the active site and substrate specificity. In this study we aim to investigate and explain the possibility of the regulatory autoinhibition process of the SMYD enzymes by a thorough computational exploration of their dynamic, energetic, and structural changes by using extended molecular dynamics simulations; normal mode analysis (NMA); and energy correlations. Three SMYD models (SMYD1-3) were used in this study. Our results showed an obvious hinge-like motion between the N- and C-lobes. Also, we identified interaction energy pathways within the 3D structures of the proteins, and hot spots on their surfaces that could be of particular importance for the regulation of their activities via allosteric means. These results can help in a better understanding of the nature of these promising drug targets; and in designing selective drugs that can interfere with (inhibit) the function of a specific SMYD member by disrupting its dynamical and conformational behaviour without disrupting the function of the entire SMYD proteins.