Lipid membrane photodamage in photodynamic therapy involves the penetration of a photosensitizer into the membrane, followed by photoactivation through intersystem crossing. The efficiency of both processes, in which electrostatic interactions with the lipid environment play a crucial role, determines the cytotoxic effect of the photosensitizer. Herein, we model the penetration of the archetypal photosensitizer methylene blue into a lipid bilayer and theoretically analyse the impact of the lipid environment on the excited state electronic structure of the photosensitizer. We show that both penetration and intersystem crossing are energetically adverse. The rationalization of the factors behind these unfavourable processes allows us to suggest some rules for the functionalization of the photosensitizer in order to improve its phototoxicity inside the lipid bilayer.
A modular short-step synthesis of the bisbenzylisoquinoline alkaloids tetrandrine and isotetrandrine was developed employing N-acyl-Pictet–Spengler reaction and Ullman diaryl ether synthesis as central steps.
Natural compounds that either increase or decrease polymerization of actin into filaments have become indispensable tools for cell biology. However, to date, it was not possible to use them as therapeutics due to their overall cytotoxicity and their unfavorable pharmacokinetics. Furthermore, their synthesis is in general quite complicated. In an attempt to find simplified analogues of miuraenamide, an actin nucleating compound, we identified derivatives with a paradoxical inversion of the mode of action: instead of increased nucleation, they caused an inhibition. Using an extensive computational approach, we propose a binding mode and a mode of action for one of these derivatives. Based on our findings, it becomes feasible to tune actin-binding compounds to one or the other direction and to generate new synthetic actin binders with increased functional selectivity.
Caseinolytic protease P (ClpP) is a tetradecameric peptidase that assembles with chaperones such as ClpX to gain proteolytic activity. Acyldepsipeptides (ADEPs) are small‐molecule mimics of ClpX that bind into hydrophobic pockets on the apical site of the complex, thereby activating ClpP. Detection of ClpP has so far been facilitated with active‐site‐directed probes which depend on the activity and oligomeric state of the complex. To expand the scope of ClpP labeling, we took a stepwise synthetic approach toward customized ADEP photoprobes. Structure–activity relationship studies with small fragments and ADEP derivatives paired with modeling studies revealed the design principles for suitable probe molecules. The derivatives were tested for activation of ClpP and subsequently applied in labeling studies of the wild‐type peptidase as well as enzymes bearing mutations at the active site and an oligomerization sensor. Satisfyingly, the ADEP photoprobes provided a labeling readout of ClpP independent of its activity and oligomeric state.
Macrocycles are interesting molecules with unique features due to their conformationally constrained yet flexible ring structure. This characteristic poses a difficult challenge for computational modeling studies since they rely on accurate structural descriptions. In particular, molecular docking calculations suffer from the lack of ring flexibility during pose generation, which is often compensated by using pregenerated ligand conformer ensembles. Moreover, receptor structures are mainly treated rigidly, which limits the use of many docking tools. In this study, we optimized our previous molecular dynamics-based sampling and docking pipeline specifically designed for the accurate prediction of macrocyclic compounds. We developed a dihedral classification procedure for in-depth conformational analysis of the macrocyclic rings and extracted structural ensembles that were subsequently docked in both bound and unbound protein structures employing a fully flexible approach. Our results suggest that including a ring conformer close to the bound state in the starting ensemble increases the chance of successful docking. The bioactive conformations of a diverse set of ligands could be predicted with high and decent accuracy in bound and unbound protein structures, respectively, due to the incorporation of full molecular flexibility in our approach. The remaining unsuccessful docking calculations were mainly caused by large flexible substituents that bind to surface-exposed binding sites, rather than the macrocyclic ring per se and could be further improved by explicit molecular dynamics simulations of the docked complex.
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