Structure-based design of promising natural products to inhibit thymidylate kinase from Monkeypox virus and validation using free energy calculations.

Monkeypox (MPXV) is a globally growing public health concern with 80,328 active cases and 53 deaths have been reported. No specific vaccine or drug is available for the treatment of MPXV. Hence, the current study also employed structure-based drug designing, molecular simulation, and free energy calculation methods to identify potential hit molecules against the TMPK of MPXV, which is a replicatory protein that helps the virus to replicate its DNA and increase the number of DNAs in the host cell. The 3D structure of TMPK was modeled with AlphaFold and screening of multiple natural products libraries (4,71,470 compounds) identified TCM26463, TCM2079, and TCM29893 from traditional Chinese medicines database (TCM), SANC00240, SANC00984, and SANC00986 South African natural compounds database (SANCDB), NPC474409, NPC278434 and NPC158847 from NPASS (natural product activity and species source database) while CNP0404204, CNP0262936, and CNP0289137 were shortlisted from coconut database (collection of open natural products) as the best hits. These compounds interact with the key active site residues through hydrogen bonds, salt bridges, and pie-pie interactions. The structural dynamics and binding free energy results further revealed that these compounds possess stable dynamics with excellent binding free energy scores. Moreover, the dissociation constant (KD) and bioactivity analysis revealed stronger activity of these compounds exhibit stronger biological activity against MPXV and may inhibit it in in vitro conditions. All the results demonstrated that the designed novel compounds possess stronger inhibitory activity than the control complex (TPD-TMPK) from the vaccinia virus. The current study is the first to design small molecule inhibitors for the replication protein of MPXV which may help in controlling the current epidemic and also overcome the challenge of vaccine evasion.

A Novel Fetal Movement Simulator for the Performance Evaluation of Vibration Sensors for Wearable Fetal Movement Monitors.

Fetal movements (FM) are an important factor in the assessment of fetal health. However, there is currently no reliable way to monitor FM outside clinical environs. While extensive research has been carried out using accelerometer-based systems to monitor FM, the desired accuracy of detection is yet to be achieved. A major challenge has been the difficulty of testing and calibrating sensors at the pre-clinical stage. Little is known about fetal movement features, and clinical trials involving pregnant women can be expensive and ethically stringent. To address these issues, we introduce a novel FM simulator, which can be used to test responses of sensor arrays in a laboratory environment. The design uses a silicon-based membrane with material properties similar to that of a gravid abdomen to mimic the vibrations due to fetal kicks. The simulator incorporates mechanisms to pre-stretch the membrane and to produce kicks similar to that of a fetus. As a case study, we present results from a comparative study of an acoustic sensor, an accelerometer, and a piezoelectric diaphragm as candidate vibration sensors for a wearable FM monitor. We find that the acoustic sensor and the piezoelectric diaphragm are better equipped than the accelerometer to determine durations, intensities, and locations of kicks, as they have a significantly greater response to changes in these conditions than the accelerometer. Additionally, we demonstrate that the acoustic sensor and the piezoelectric diaphragm can detect weaker fetal movements (threshold wall displacements are less than 0.5 mm) compared to the accelerometer (threshold wall displacement is 1.5 mm) with a trade-off of higher power signal artefacts. Finally, we find that the piezoelectric diaphragm produces better signal-to-noise ratios compared to the other two sensors in most of the cases, making it a promising new candidate sensor for wearable FM monitors. We believe that the FM simulator represents a key development towards enabling the eventual translation of wearable FM monitoring garments.