Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor.

Back in Person: Frontiers in Medicinal Chemistry 2023.

The Frontiers in Medicinal Chemistry (FiMC) is the largest international Medicinal Chemistry conference in the German speaking area and took place from April 3 to 5 2023 in Vienna (Austria). Fortunately, after being cancelled in 2020 and two years (2021-2022) of entirely virtual meetings, due to the COVID-19 pandemic, the FiMC could be held in a face-to-face format again. Organized by the Division of Medicinal Chemistry of the German Chemical Society (GDCh), the Division of Pharmaceutical and Medicinal Chemistry of the German Pharmaceutical Society (DPhG), together with the Division of Medicinal Chemistry of the Austrian Chemical Society (GÖCH), the Austrian Pharmaceutical Society (ÖPhG), and a local organization committee from the University of Vienna headed by Thierry Langer, the meeting brought together 260 participants from 21 countries.

Chemical space docking enables large-scale structure-based virtual screening to discover ROCK1 kinase inhibitors.

With the ever-increasing number of synthesis-on-demand compounds for drug lead discovery, there is a great need for efficient search technologies. We present the successful application of a virtual screening method that combines two advances: (1) it avoids full library enumeration (2) products are evaluated by molecular docking, leveraging protein structural information. Crucially, these advances enable a structure-based technique that can efficiently explore libraries with billions of molecules and beyond.

Frontiers in Medicinal Chemistry 2022 Goes Virtual.

The Frontiers in Medicinal Chemistry (FiMC) meeting, which represents the largest international medicinal chemistry conference in Germany, took place from March 14 to 16 2022 in a fully virtual format. Organized by the Division of Medicinal Chemistry of the German Chemical Society (GDCh) together with the Division of Pharmaceutical & Medicinal Chemistry of the German Pharmaceutical Society (DPhG) and a "local" organization committee from the University of Freiburg headed by Manfred Jung, the meeting brought together 271 participants from around 20 countries. The program included 33 lectures by leading scientists from industry and academia as well as early career investigators.

A small-molecule ARTS mimetic promotes apoptosis through degradation of both XIAP and Bcl-2.

Many human cancers over-express B cell lymphoma 2 (Bcl-2) or X-linked inhibitor of apoptosis (IAP) proteins to evade cell death. The pro-apoptotic ARTS (Sept4_i2) protein binds directly to both Bcl-2 and XIAP and promotes apoptosis by stimulating their degradation via the ubiquitin-proteasome system (UPS). Here we describe a small molecule, A4, that mimics the function of ARTS.

SAR by Space: Enriching Hit Sets from the Chemical Space.

We introduce SAR-by-Space, a concept to drastically accelerate structure-activity relationship (SAR) elucidation by synthesizing neighboring compounds that originate from vast chemical spaces. The space navigation is accomplished within minutes on affordable standard computer hardware using a tree-based molecule descriptor and dynamic programming. Maximizing the synthetic accessibility of the results from the computer is achieved by applying a careful selection of building blocks in combination with suitably chosen reactions; a decade of in-house quality control shows that this is a crucial part in the process.

Bacterial Expression and HTS Assessment of Soluble Epoxide Hydrolase Phosphatase.

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that possesses an epoxide hydrolase and lipid phosphatase activity (sEH-P) at two distinct catalytic domains. While the physiological role of the epoxide hydrolase domain is well understood, the consequences of the phosphatase activity remain unclear. Herein we describe the bacterial expression of the recombinant N-terminal domain of sEH-P and the development of a high-throughput screening protocol using a sensitive and commercially available substrate fluorescein diphosphate.

Probing metallo-β-lactamases with molecular fragments identified by consensus docking.

Bacterial resistance mediated by metallo-β-lactamases (MBLs) is a major problem for the treatment of infections. An MBL inhibitor could restore the potency of β-lactam antibiotics. Fragment-based design might deliver valuable starting points for the discovery of novel MBL inhibitors.

NSAIDs Ibuprofen, Indometacin, and Diclofenac do not interact with Farnesoid X Receptor.

The nuclear farnesoid X receptor (FXR) is a ligand activated transcription factor and acts as cellular sensor for bile acids. In this role, FXR is a highly important liver protector and FXR inhibition by antagonists or knockout has shown several deleterious effects. A recent report characterized non-steroidal anti-rheumatic drugs (NSAIDs) such as ibuprofen or diclofenac as FXR antagonists and linked hepatotoxic effects of these drugs with antagonistic activity on FXR.

Exploring the chemical space of multitarget ligands using aligned self-organizing maps.

Design of multitarget drugs and polypharmacological compounds has become popular during the past decade. However, the main approach to design such compounds is to link two selective ligands via a flexible linker. Although such chimeric ligands often have reasonable potency in vitro, the in vivo efficacy is low due to high molecular weight, low ligand efficiency, and poor pharmacokinetic profile.

From a multipotent stilbene to soluble epoxide hydrolase inhibitors with antiproliferative properties.

Inspired by nature: Natural product isopropylstilbene was identified as an inhibitor of soluble epoxide hydrolase exhibiting antiproliferative properties. Following the natural product inspired design approach, a library of (E)-styryl-1H-benzo[d]imidazoles was synthesized and evaluated with recombinant enzyme and on several cancer cell lines.

Synthesis and structure-activity relationship studies of novel dual inhibitors of soluble epoxide hydrolase and 5-lipoxygenase.

Current research leads to the assumption that drugs affecting more than one target could result in a more efficient treatment of diseases and fewer safety concerns. Administration of drugs inhibiting only one branch of the arachidonic acid cascade is usually accompanied by side effects. We therefore designed and synthesized a library of hybrid molecules incorporating an imidazo[1,2-a]pyridine and an urea moiety as novel soluble epoxide hydrolase (sEH)/5-lipoxygenase (5-LO) dual inhibitors.

Design and synthesis of dual modulators of soluble epoxide hydrolase and peroxisome proliferator-activated receptors.

Metabolic syndrome is a complex condition which often requires the use of multiple medications as a treatment. The resulting problems of polypharmacy are increase in side effects, drug-drug interactions, and its high economic cost. Development of multitarget compounds is a promising strategy to avoid the complications arising from administration of multiple drugs.

Evaluation of structure-derived pharmacophore of soluble epoxide hydrolase inhibitors by virtual screening.

The soluble epoxide hydrolase (sEH) is an enzyme located downstream of the CYP 450 branch of the arachidonic acid cascade and can be linked to a number of indications, including cardiovascular disorders, diabetes and inflammatory processes. Numerous inhibitors (sEHI) have been reported, mostly based on urea or amide scaffolds. The search for valid bioisosteric replacements is an ongoing challenge in the discovery of sEHI.

Dual-target virtual screening by pharmacophore elucidation and molecular shape filtering.

Dual-target inhibitors gained increased attention in the past years. A novel in silico approach was employed for the discovery of dual 5-lipoxygenase/soluble epoxide hydrolase inhibitors. The ligand-based approach uses excessive pharmacophore elucidation and pharmacophore alignment in conjunction with shape-based scoring.