5 research outputs found
Structure-Activity Relationships of Triple-Action Platinum(IV) Prodrugs with Albumin-Binding Properties and Immunomodulating Ligands
Chemotherapy with
platinum complexes is essential for clinical
anticancer therapy. However, due to side effects and drug resistance,
further drug improvement is urgently needed. Herein, we report on
triple-action platinumÂ(IV) prodrugs, which, in addition to tumor targeting via maleimide-mediated albumin binding, release the immunomodulatory
ligand 1-methyl-d-tryptophan (1-MDT). Unexpectedly, structure–activity
relationship analysis showed that the mode of 1-MDT conjugation distinctly
impacts the reducibility and thus activation of the prodrugs. This
in turn affected ligand release, pharmacokinetic properties, efficiency
of immunomodulation, and the anticancer activity in vitro and in a mouse model in vivo. Moreover, we could
demonstrate that the design of albumin-targeted multi-modal prodrugs
using platinumÂ(IV) is a promising strategy to enhance the cellular
uptake of bioactive ligands with low cell permeability (1-MDT) and
to improve their selective delivery into the malignant tissue. This
will allow tumor-specific anticancer therapy supported by a favorably
tuned immune microenvironment
Supervised Molecular Dynamics (SuMD) Approaches in Drug Design
Supervised MD (SuMD) is a computational method that enables the exploration of ligand-receptor recognition pathway in a reduced timescale. The performance speedup is due to the incorporation of a tabu-like supervision algorithm on the ligand-receptor approaching distance into a classic molecular dynamics (MD) simulation. SuMD enables the investigation of ligand-receptor binding events independently from the starting position, chemical structure of the ligand (small molecules or peptides), and also from its receptor-binding affinity. The application of SuMD highlights an appreciable capability of the technique to reproduce the crystallographic structures of several ligand-protein complexes and can provide high-quality protein-ligand models of for which yet experimental confirmation of binding mode is not available
Structural insights into binding specificity, efficacy and bias of a β <sub>2</sub> AR partial agonist
Salmeterol is a partial agonist for the β2 adrenergic receptor (β2AR) and the first long-acting β2AR agonist to be widely used clinically for the treatment of asthma and chronic obstructive pulmonary disease. Salmeterol's safety and mechanism of action have both been controversial. To understand its unusual pharmacological action and partial agonism, we obtained the crystal structure of salmeterol-bound β2AR in complex with an active-state-stabilizing nanobody. The structure reveals the location of the salmeterol exosite, where sequence differences between β1AR and β2AR explain the high receptor-subtype selectivity. A structural comparison with the β2AR bound to the full agonist epinephrine reveals differences in the hydrogen-bond network involving residues Ser2045.43 and Asn2936.55. Mutagenesis and biophysical studies suggested that these interactions lead to a distinct active-state conformation that is responsible for the partial efficacy of G-protein activation and the limited β-arrestin recruitment for salmeterol