Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets.     

Inter‐serotype reassortment among epizootic haemorrhagic disease viruses in the United States

First described in 1955 in New Jersey, epizootic haemorrhagic disease (EHD) causes a severe clinical disease in wild and domestic ruminants worldwide. Epizootic haemorrhagic disease outbreaks occur in deer populations each year from summer to late autumn. The etiological agent is EHD virus (EHDV) which is a double‐stranded segmented icosahedral RNA virus. EHD virus utilizes point mutations and reassortment strategies to maintain viral fitness during infection. In 2018, EHDV serotype 2 was predominantly detected in deer in Illinois. Whole genome sequencing was conducted for two 2018 EHDV2 isolates (IL41747 and IL42218) and the sequence analyses indicated that IL42218 was a reassortant between different serotypes whereas IL41747 was a genetically stable strain. Our data suggest that multiple strains contribute to outbreaks each year.     

Does Rest Time before Ultrasonography Imaging Affect Quadriceps Femoris Muscle Thickness,Cross-Sectional Area and Echo Intensity Measurements?

In the work described here, our aim was to determine, in an elderly population, changes in muscle thickness (MT), cross-sectional area (CSA) and echo intensity (EI) of the quadriceps muscles at four time points (0, 5, 10 and 15 min; i.e., T0, T5, T10 and T15, respectively) after changing from a standing to supine position. Twenty-one elderly participants (14 men: 68.1 ± 4.6 y; 8 women: 66.8 ± 4.1 y) were evaluated at four time points. Rectus femoris CSA (RF_CSA), MT and EI of the quadriceps femoris (QF) muscles were assessed. EI significantly increased from T0 to T5, T10 and T15 (p < 0.001), whereas no differences were observed between T5 and T15 in the rectus femoris (RF_EI), vastus intermedius (VI_EI) and quadriceps femoris (QF_EI). No differences were observed between any time points in the RF_CSA and MT of QF muscles. In summary, these results suggest that periods >5 min are not necessary to obtain consistent MT and EI measurements of quadriceps femoris muscles in the elderly population.