Identifying natural product inhibitors against CDK9 enzyme via combined multicomplex-based pharmacophore modeling, interaction studies and molecular dynamics simulations.

In the current work, multicomplex-based pharmacophore modeling was performed on the CDK9 enzyme. The generated models possess five, four, and six features, which were subjected to the validation process. Among them, six feature models were selected as representative models to conduct the virtual screening process. The screened drug-like candidates were chosen to perform molecular docking to study their interaction patterns within the binding cavity of the CDK9 protein. Based on the docking score and presence of crucial interactions, out of 780 filtered candidates, only 205 were docked. These docked candidates were further accessed via HYDE assessment. Based on ligand efficiency and Hyde score, only nine candidates passed the criteria. The stability of these nine complexes, along with the reference, was studied by molecular dynamics simulations. Out of nine, only seven displayed stable behaviour during the simulations, and their stability was further assessed by molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA)-based free binding energy calculations and per residue contribution. From the present contribution, we obtained seven unique scaffolds that can be utilized as the starting lead for the development of CDK9 anticancer compounds.

Is COVID-19 Gender-sensitive?

While clinical characteristics exhibit that susceptibility to COVID-19 infection is equally likely between males and females, clinical outcomes show that males experience both a higher severity and fatality for COVID-19 infection than females. This review examines the evidence for these sex and gender differences and aims to illustrate possible mechanisms behind such sensitivity. Successful entry of SARS-CoV-2 into the body is dependent on the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane protease serine 2 (TMPRSS2). Thus, sex-based differences in the expression of the ACE2 receptor and TMPRSS2 may explain the disparities in COVID-19 severity and fatality. Furthermore, these disparities may also be attributed to sex-based difference in immunological responses. Finally, the differences in clinical outcomes of COVID-19 infections between men and women may be due to gendered differences in behaviors, such as smoking, and prevalence to comorbidities. An understanding of the sex and gender sensitivities of COVID-19 infection is a necessary component towards the creation of effective treatment options and therapies for the virus. Graphical abstract.

Redox-activated manganese-based MR contrast agent.

Here we report a simple Mn coordination complex with utility as a redox-sensitive MR probe. The HBET ligand stabilizes both the Mn(2+) and Mn(3+) oxidation states. In the presence of glutathione (GSH), low relaxivity Mn(III)-HBET is converted to high relaxivity Mn(II)-HBET with a 3-fold increase in relaxivity, and concomitant increase in MR signal. Alternately, hydrogen peroxide can convert Mn(II)-HBET to Mn(III)-HBET with a reduction in MR signal.

"Squaring the clusters": a Mn(III)4Ni(II)4 molecular square from nickel(II)-induced structural transformation of a Mn(II/III/IV)12 cage.

A Mn(III)(4)Ni(II)(4) molecular square exhibiting slow magnetization relaxation has been prepared from the reaction of a Mn(II)(4)Mn(III)(6)Mn(IV)(2) cluster and a simple Ni(II) source.

Synthetic model of the asymmetric [Mn3CaO4] cubane core of the oxygen-evolving complex of photosystem II.

The laboratory synthesis of the oxygen-evolving complex (OEC) of photosystem II has been the objective of synthetic chemists since the early 1970s. However, the absence of structural information on the OEC has hampered these efforts. Crystallographic reports on photosystem II that have been appearing at ever-improving resolution over the past ten years have finally provided invaluable structural information on the OEC and show that it comprises a [Mn(3)CaO(4)] distorted cubane, to which is attached a fourth, external Mn atom, and the whole unit attached to polypeptides primarily by aspartate and glutamate carboxylate groups. Such a heterometallic Mn/Ca cubane with an additional metal attached to it has been unknown in the literature. This paper reports the laboratory synthesis of such an asymmetric cubane-containing compound with a bound external metal atom, [(1)]. All peripheral ligands are carboxylate or carboxylic acid groups. Variable-temperature magnetic susceptibility data have established 1 to possess an S = 9/2 ground state. EPR spectroscopy confirms this, and the Davies electron nuclear double resonance data reveal similar hyperfine couplings to those of other Mn(IV) species, including the OEC S(2) state. Comparison of the X-ray absorption data with those for the OEC reveal 1 to possess structural parameters that make it a close structural model of the asymmetric-cubane OEC unit. This geometric and electronic structural correspondence opens up a new front in the multidisciplinary study of the properties and function of this important biological unit.