Pandemic drugs at pandemic speed: infrastructure for accelerating COVID-19 drug discovery with hybrid machine learning- and physics-based simulations on high-performance computers.

The race to meet the challenges of the global pandemic has served as a reminder that the existing drug discovery process is expensive, inefficient and slow. There is a major bottleneck screening the vast number of potential small molecules to shortlist lead compounds for antiviral drug development. New opportunities to accelerate drug discovery lie at the interface between machine learning methods, in this case, developed for linear accelerators, and physics-based methods.

N-Terminus to Arginine Side-Chain Cyclization of Linear Peptidic Neuropeptide Y Y Receptor Ligands Results in Picomolar Binding Constants.

The family of neuropeptide Y (NPY) receptors comprises four subtypes (YR, YR, YR, YR), which are addressed by at least three endogenous peptides, i.e., NPY, peptide YY, and pancreatic polypeptide (PP), the latter showing a preference for YR.

Dibenzodiazepinone-type muscarinic receptor antagonists conjugated to basic peptides: Impact of the linker moiety and unnatural amino acids on MR selectivity.

The family of human muscarinic acetylcholine receptors (MRs) is characterized by a high sequence homology among the five subtypes (MR-MR), being the reason for a lack of subtype selective MR ligands. In continuation of our work on dualsteric dibenzodiazepinone-type MR antagonists, a series of MR ligands containing a dibenzodiazepinone pharmacophore linked to small basic peptides was synthesized (64 compounds). The linker moiety was varied with respect to length, number of basic nitrogens (0-2) and flexibility.

Argininamide-type neuropeptide Y Y receptor antagonists: the nature of -carbamoyl substituents determines YR binding mode and affinity.

The recently resolved crystal structure of the neuropeptide Y Y receptor (YR), co-crystallized with the high-affinity (p : 10.11), argininamide-type YR antagonist UR-MK299 (), revealed that the -carbamoyl substituent (van der Waals volume: 139 Å) is deeply buried in the receptor, occupying a hydrophobic pocket. We synthesized and characterized a series of argininamides, structurally related to .

Water-soluble inhibitors of ABCG2 (BCRP) - A fragment-based and computational approach.

A good balance between hydrophilicity and lipophilicity is a prerequisite for all bioactive compounds. If the hydrophilicity of a compound is low, its solubility in water will be meager. Many drug development failures have been attributed to poor aqueous solubility.

Oligopeptides as Neuropeptide Y Y Receptor Ligands: Identification of a High-Affinity Tetrapeptide Agonist and a Hexapeptide Antagonist.

Within the family of neuropeptide Y (NPY) receptors, the Y receptor (YR) is unique as it prefers pancreatic polypeptide over NPY and peptide YY. Today, low-molecular-weight YR ligands are lacking, in particular antagonists. We synthesized a series of peptidic NPY YR ligands, derived from the hexapeptide acetyl-Arg-Tyr-Arg-Leu-Arg-Tyr-NH (), reported to be a YR partial agonist with high affinity (p YR: 8.

UR-DEBa242: A Py-5-Labeled Fluorescent Multipurpose Probe for Investigations on the Histamine H and H Receptors.

Comprehensively characterized fluorescent probes for the histamine H receptor (HR) and especially for the HR orthologs [e.g., human (h) and mouse (m)] are highly needed as versatile complementary tools to radioligands.

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M Receptor.

Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high MR affinities (p (radioligand competition binding): 9.10-9.

Basal Histamine H Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif.

Histamine H receptor (H R) orthologues are G-protein-coupled receptors (GPCRs) that exhibit species-dependent basal activity. In contrast to the basally inactive mouse H R (mH R), human H R (hH R) shows a high degree of basal activity. We have performed long-timescale molecular dynamics simulations and rigidity analyses on wild-type hH R, the experimentally characterized hH R variants S179M, F169V, F169V+S179M, F168A, and on mH R to investigate the molecular nature of the differential basal activity.

Universal Activation Index for Class A GPCRs.

An index of the activation of Class A G-protein-coupled receptors (GPCRs) has been trained using interhelix distances from a series of microsecond molecular-dynamics simulations and tested for 268 published X-ray structures. In a three-class model that includes intermediate structures, 63% of the active structures are classified in agreement with the experimental assignment, 81% of the intermediate structures, and 89% of the inactives. An alternative two-state model classifies 94% of the actives and 99% of the inactives correctly.

Conjugation of Short Peptides to Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Determines MR Selectivity.

Muscarinic acetylcholine receptors (MRs), comprising five subtypes (MR-MR) in humans, exhibit a high degree of structural similarity. Therefore, subtype-selective MR agonists and antagonists are lacking. We present an approach to highly MR-selective MR antagonists based on the conjugation of di- or tripeptides to MR-preferring dibenzodiazepinone-type MR antagonists.

Structure-Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands.

New classes of alkylated hetarylpropylguanidines with different functionality and variation in spacer length were synthesized to determine their behavior at the four histamine receptor (HR, HR, HR, HR) subtypes. Alkylated guanidines with different terminal functional groups and varied basicity, like amine, guanidine and urea were developed, based on the lead structure SK&F 91486 (). Furthermore, heteroatomic exchange at the guanidine structure of led to simple analogues of the lead compound.

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H Receptor Agonists.

On the basis of the long-known prototypic pharmacophore 3-(1-imidazol-4-yl)propylguanidine (SK&F 91486, ), monomeric, homodimeric, and heterodimeric bisalkylguanidine-type histamine H receptor (HR) agonists with various alkyl spacers were synthesized. Aiming at increased HR selectivity of the ligands, the imidazol-4-yl moiety was replaced by imidazol-1-yl, 2-aminothiazol-5-yl or 2-amino-4-methylthiazol-5-yl according to a bioisosteric approach. All compounds turned out to be partial or full agonists at the //HR.

Structural basis of ligand binding modes at the neuropeptide Y Y receptor.

Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology . The NPY-Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in most mammals, namely the Y, Y, Y and Y receptors, with different affinity and selectivity . NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y receptor (YR) .

Radiolabeled Dibenzodiazepinone-Type Antagonists Give Evidence of Dualsteric Binding at the M Muscarinic Acetylcholine Receptor.

The dualsteric ligand approach, aiming at ligands with improved subtype selectivity, has been increasingly applied to muscarinic receptors (MRs). In this article, we present the synthesis and characterization of a MR subtype-preferring radiolabeled dibenzodiazepinone-type antagonist ([H]UNSW-MK259, [H]19) and its homodimeric analogue [H]UR-AP060 ([H]33). Saturation binding studies at the MR, using the orthosteric antagonist atropine to determine unspecific binding, proved that the monomeric and the dimeric compound bind to the orthosteric binding site (apparent K: 0.

Mimicking of Arginine by Functionalized N(ω)-Carbamoylated Arginine As a New Broadly Applicable Approach to Labeled Bioactive Peptides: High Affinity Angiotensin, Neuropeptide Y, Neuropeptide FF, and Neurotensin Receptor Ligands As Examples.

Derivatization of biologically active peptides by conjugation with fluorophores or radionuclide-bearing moieties is an effective and commonly used approach to prepare molecular tools and diagnostic agents. Whereas lysine, cysteine, and N-terminal amino acids have been mostly used for peptide conjugation, we describe a new, widely applicable approach to peptide conjugation based on the nonclassical bioisosteric replacement of the guanidine group in arginine by a functionalized carbamoylguanidine moiety. Four arginine-containing peptide receptor ligands (angiotensin II, neurotensin(8-13), an analogue of the C-terminal pentapeptide of neuropeptide Y, and a neuropeptide FF analogue) were subject of this proof-of-concept study.

The extracellular loop 2 (ECL2) of the human histamine H4 receptor substantially contributes to ligand binding and constitutive activity.

In contrast to the corresponding mouse and rat orthologs, the human histamine H4 receptor (hH4R) shows extraordinarily high constitutive activity. In the extracellular loop (ECL), replacement of F169 by V as in the mouse H4R significantly reduced constitutive activity. Stabilization of the inactive state was even more pronounced for a double mutant, in which, in addition to F169V, S179 in the ligand binding site was replaced by M.

Luciferase reporter gene assay on human, murine and rat histamine H4 receptor orthologs: correlations and discrepancies between distal and proximal readouts.

The investigation of the (patho)physiological role of the histamine H4 receptor (H4R) and its validation as a possible drug target in translational animal models are compromised by distinct species-dependent discrepancies regarding potencies and receptor subtype selectivities of the pharmacological tools. Such differences were extremely pronounced in case of proximal readouts, e. g.