4 research outputs found
Targeting Dynamic Pockets of HIVā1 Protease by Structure-Based Computational Screening for Allosteric Inhibitors
We
present the discovery of low molecular weight inhibitors of
human immunodeficiency virus 1 (HIV-1) protease subtype B that were
identified by structure-based virtual screening as ligands of an allosteric
surface cavity. For pocket identification and prioritization, we performed
a molecular dynamics simulation and observed several flexible, partially
transient surface cavities. For one of these presumable ligand-binding
pockets that are located in the so-called āhinge regionā
of the identical protease chains, we computed a receptor-derived pharmacophore
model, with which we retrieved fragment-like inhibitors from a screening
compound pool. The most potent hit inhibited protease activity in
vitro in a noncompetitive mode of action. Although attempts failed
to crystallize this ligand bound to the enzyme, the study provides
proof-of-concept for identifying innovative tool compounds for chemical
biology by addressing flexible protein models with receptor pocket-derived
pharmacophore screening
Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists Specifically Optimized for Multidose Formulations
Novel peptidic dual
agonists of the glucagon-like peptide 1 (GLP-1)
and glucagon receptor are reported to have enhanced efficacy over
pure GLP-1 receptor agonists with regard to treatment of obesity and
diabetes. We describe novel exendin-4 based dual agonists designed
with an activity ratio favoring the GLP-1 versus the glucagon receptor.
As result of an iterative optimization procedure that included molecular
modeling, structural biological studies (X-ray, NMR), peptide design
and synthesis, experimental activity, and solubility profiling, a
candidate molecule was identified. Novel SAR points are reported that
allowed us to fine-tune the desired receptor activity ratio and increased
solubility in the presence of antimicrobial preservatives, findings
that can be of general applicability for any peptide discovery project.
The peptide was evaluated in chronic <i>in vivo</i> studies
in obese diabetic monkeys as translational model for the human situation
and demonstrated favorable blood glucose and body weight lowering
effects
Probing Factor Xa ProteināLigand Interactions: Accurate Free Energy Calculations and Experimental Validations of Two Series of High-Affinity Ligands
The accurate prediction of proteināligand binding
affinity
belongs to one of the central goals in computer-based drug design.
Molecular dynamics (MD)-based free energy calculations have become
increasingly popular in this respect due to their accuracy and solid
theoretical basis. Here, we present a combined study which encompasses
experimental and computational studies on two series of factor Xa
ligands, which enclose a broad chemical space including large modifications
of the central scaffold. Using this integrated approach, we identified
several new ligands with different heterocyclic scaffolds different
from the previously identified indole-2-carboxamides that show superior
or similar affinity. Furthermore, the so far underexplored terminal
alkyne moiety proved to be a suitable non-classical bioisosteric replacement
for the higher halogenāĻ aryl interactions. With this
challenging example, we demonstrated the ability of the MD-based non-equilibrium
free energy calculation approach for guiding crucial modifications
in the lead optimization process, such as scaffold replacement and
single-site modifications at molecular interaction hot spots
Novel Ī²āAmino Acid Derivatives as Inhibitors of Cathepsin A
Cathepsin A (CatA) is a serine carboxypeptidase distributed
between
lysosomes, cell membrane, and extracellular space. Several peptide
hormones including bradykinin and angiotensin I have been described
as substrates. Therefore, the inhibition of CatA has the potential
for beneficial effects in cardiovascular diseases. Pharmacological
inhibition of CatA by the natural product ebelactone B increased renal
bradykinin levels and prevented the development of salt-induced hypertension.
However, so far no small molecule inhibitors of CatA with oral bioavailability
have been described to allow further pharmacological profiling. In
our work we identified novel Ī²-amino acid derivatives as inhibitors
of CatA after a HTS analysis based on a project adapted fragment approach.
The new inhibitors showed beneficial ADME and pharmacokinetic profiles,
and their binding modes were established by X-ray crystallography.
Further investigations led to the identification of a hitherto unknown
pathophysiological role of CatA in cardiac hypertrophy. One of our
inhibitors is currently undergoing phase I clinical trials