Covalent Fragments Acting as Tyrosine Mimics for Mutant p53-Y220C Rescue by Nucleophilic Aromatic Substitution.

The tumor suppressor p53 is frequently mutated in human cancers. The Y220C mutant is the ninth most common p53 cancer mutant and is classified as a structural mutant, as it leads to strong thermal destabilization and degradation by creating a solvent-accessible hydrophobic cleft. To identify small molecules that thermally stabilize p53, we employed DSF to screen SAr-type electrophiles from our covalent fragment library (CovLib) for binding to different structural (Y220C, R282W) and DNA contact (R273H) mutants of p53.

Halogen Bonding on Water─A Drop in the Ocean?

Halogen bonding is a valuable interaction in drug design, offering an unconventional way to influence affinity and selectivity by leveraging the halogen atoms' ability to form directional bonds. The present study evaluates halogen-water interactions within protein binding sites, demonstrating that targeting a water molecule via halogen bonding can in specific cases contribute beneficially to ligand binding. In solving and examining the crystal structure of 2-cyclopentyl-7-iodo-1-indole-3-carbonitrile bound to DYRK1a kinase, we identified a notable iodine-water interaction, where water accepts a halogen bond with good geometric and energetic features.

Evaluation of a Covalent Library of Diverse Warheads (CovLib) Binding to JNK3, USP7, or p53.

Purpose: Over the last few years, covalent fragment-based drug discovery has gained significant importance. Thus, striving for more warhead diversity, we conceived a library consisting of 20 covalently reacting compounds. Our covalent fragment library (CovLib) contains four different warhead classes, including five α-cyanoacacrylamides/acrylates (CA), three epoxides (EO), four vinyl sulfones (VS), and eight electron-deficient heteroarenes with a leaving group (SAr/SN).

Principles and Applications of CFX Moieties as Unconventional Halogen Bond Donors in Medicinal Chemistry, Chemical Biology, and Drug Discovery.

As an orthogonal principle to the established (hetero)aryl halides, we herein highlight the usefulness of CFX (X = Cl, Br, or I) moieties. Using tool compounds bearing CFX moieties, we study their chemical/metabolic stability and their logP/solubility, as well as the role of XB in their small molecular crystal structures. Employing QM techniques, we analyze the observed interactions, provide insights into the conformational flexibilities and preferences in the potential interaction space.

Synthesis of Amino Acids Bearing Halodifluoromethyl Moieties and Their Application to p53-Derived Peptides Binding to Mdm2/Mdm4.

Introduction: Therapeutic peptides are a significant class of drugs in the treatment of a wide range of diseases. To enhance their properties, such as stability or binding affinity, they are usually chemically modified. This includes, among other techniques, cyclization of the peptide chain by bridging, modifications to the backbone, and incorporation of unnatural amino acids.

Targeting of Fascin Protein for Cancer Therapy: Benchmarking, Virtual Screening and Molecular Dynamics Approaches.

Fascin is an actin-bundling protein overexpressed in various invasive metastatic carcinomas through promoting cell migration and invasion. Therefore, blocking Fascin binding sites is considered a vital target for antimetastatic drugs. This inspired us to find new Fascin binding site blockers.

Revisiting a challenging p53 binding site: a diversity-optimized HEFLib reveals diverse binding modes in T-p53C-Y220C.

The cellular tumor antigen p53 is a key component in cell cycle control. The mutation Y220C heavily destabilizes the protein thermally but yields a druggable crevice. We have screened the diversity-optimized halogen-enriched fragment library against T-p53C-Y220C with STD-NMR and DSF to identify hits, which we validated by H,N-HSQC NMR.

Screening of a Halogen-Enriched Fragment Library Leads to Unconventional Binding Modes.

We conceived the Halogen-Enriched Fragment Library (HEFLib) to investigate the potential of halogen bonds in the early stages of drug discovery. As the number of competitive interactions increases with ligand size, we reasoned that a binding mode relying on halogen bonding is more likely for fragments than highly decorated molecules. Thus, fragments could feature unexplored binding modes.

Discovery of Ircinianin Lactones B and C-Two New Cyclic Sesterterpenes from the Marine Sponge .

Two new ircinianin-type sesterterpenoids, ircinianin lactone B and ircinianin lactone C ( and ), together with five known entities from the ircinianin compound family (, -) were isolated from the marine sponge . Ircinianin lactones B and C ( and ) represent new ircinianin terpenoids with a modified oxidation pattern. Despite their labile nature, the structures could be established using a combination of spectroscopic data, including HRESIMS and 1D/2D NMR techniques, as well as computational chemistry and quantum-mechanical calculations.

Quadruple Target Evaluation of Diversity-Optimized Halogen-Enriched Fragments (HEFLibs) Reveals Substantial Ligand Efficiency for AP2-Associated Protein Kinase 1 (AAK1).

Fragment-based drug discovery is one of the most utilized approaches for the identification of novel weakly binding ligands, by efficiently covering a wide chemical space with rather few compounds and by allowing more diverse binding modes to be found. This approach has led to various clinical candidates and approved drugs. Halogen bonding, on the other hand, has gained traction in molecular design and lead optimization, but could offer additional benefits in early drug discovery.

Facilitating SARS CoV-2 RNA-Dependent RNA polymerase (RdRp) drug discovery by the aid of HCV NS5B palm subdomain binders: In silico approaches and benchmarking.

Corona Virus 2019 Disease (COVID-19) is a rapidly emerging pandemic caused by a newly discovered beta coronavirus, called Sever Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2). SARS CoV-2 is an enveloped, single stranded RNA virus that depends on RNA-dependent RNA polymerase (RdRp) to replicate. Therefore, SARS CoV-2 RdRp is considered as a promising target to cease virus replication.

Supporting SARS-CoV-2 Papain-Like Protease Drug Discovery: Methods and Benchmarking.

The coronavirus disease 19 (COVID-19) is a rapidly growing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its papain-like protease (SARS-CoV-2 PLpro) is a crucial target to halt virus replication. SARS-CoV PLpro and SARS-CoV-2 PLpro share an 82.

Small-Molecule Intervention At The Dimerization Interface Of Survivin By Novel Rigidized Scaffolds.

Introduction: Survivin is a nodal protein involved in several cellular pathways. It is a member of the IAP family and an integral component of the chromosomal passenger complex, where it binds to borealin and INCENP through its dimerization interface. By targeting survivin with a small molecule at its dimerization interface, inhibition of the proliferation of cancer cells has been suggested.

Synthesis, in vitro biological evaluation and in silico studies of certain arylnicotinic acids conjugated with aryl (thio)semicarbazides as a novel class of anti-leishmanial agents.

Herein we introduce new compounds as conjugates of arylnicotinic acids with aryl (thio)semicarbazide derivatives. Based on a structure-guided approach, they were designed to possess anti-leishmanial activity through anti-folate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm-PTR1). The in vitro anti-promastigote and anti-amastigote activity were promising for many thiosemicarbazide derivatives and superior to the reference miltefosine.

Embracing the Diversity of Halogen Bonding Motifs in Fragment-Based Drug Discovery-Construction of a Diversity-Optimized Halogen-Enriched Fragment Library.

Halogen bonds have recently gained attention in life sciences and drug discovery. However, it can be difficult to harness their full potential, when newly introducing them into an established hit or lead structure by molecular design. A possible solution to overcome this problem is the use of halogen-enriched fragment libraries (HEFLibs), which consist of chemical probes that provide the opportunity to identify halogen bonds as one of the main features of the binding mode.

Scaffold Effects on Halogen Bonding Strength.

Halogen bonds have become increasingly popular interactions in molecular design and drug discovery. One of the key features is the strong dependence of the size and magnitude of the halogen's σ-hole on the chemical environment of the ligand. The term σ-hole refers to a region of lower electronic density opposite to a covalent bond, e.

Predicting the Magnitude of σ-Holes Using VmaxPred, a Fast and Efficient Tool Supporting the Application of Halogen Bonds in Drug Discovery.

Halogen bonding as a modern molecular interaction has received increasing attention not only in materials sciences but also in biological systems and drug discovery. Thus, there is a growing demand for fast, efficient, and easily applicable tailor-made tools supporting the use of halogen bonds in molecular design and medicinal chemistry. The potential strength of a halogen bond is dependent on several properties of the σ-hole donor, e.

The Symmetric Tetravalent Sulfhydryl-Specific Linker NATBA Facilitates a Combinatorial "Tool Kit" Strategy for Phage Display-Based Selection of Functionalized Bicyclic Peptides.

The rigid conformation of constrained bicyclic peptides provides a number of advantages over larger protein-based ligands, including better chemical stability, enhanced tissue penetration, and a wider field of possible applications. Selective chemical modification strategies are able to extend the scope of applications not only in a therapeutic manner but also for the development of novel tools for protein capturing, bioimaging, and targeted drug delivery. Herein, we report the synthesis of an adamantane-based, symmetrical, tetravalent, sulfhydryl-specific peptide linker.

Switching Between Bicyclic and Linear Peptides - The Sulfhydryl-Specific Linker TPSMB Enables Reversible Cyclization of Peptides.

Phage display-selected bicyclic peptides have already shown their great potential for the development as bioactive modulators of therapeutic targets. They can provide enhanced proteolytic stability and improved membrane permeability. Molecular design of new linker molecules has led to a variety of new synthetic approaches for the generation of chemically constrained cyclic peptides.

Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38α Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3.

Starting from known p38α mitogen-activated protein kinase (MAPK) inhibitors, a series of inhibitors of the c-Jun N-terminal kinase (JNK) 3 was obtained. Altering the substitution pattern of the pyridinylimidazole scaffold proved to be effective in shifting the inhibitory activity from the original target p38α MAPK to the closely related JNK3. In particular, a significant improvement for JNK3 selectivity could be achieved by addressing the hydrophobic region I with a small methyl group.

Symmetric dimeric adamantanes for exploring the structure of two viroporins: influenza virus M2 and hepatitis C virus p7.

Background: Adamantane-based compounds have been identified to interfere with the ion-channel activity of viroporins and thereby inhibit viral infection. To better understand the difference in the inhibition mechanism of viroporins, we synthesized symmetric dimeric adamantane analogs of various alkyl-spacer lengths.

Methods: Symmetric dimeric adamantane derivatives were synthesized where two amantadine or rimantadine molecules were linked by various alkyl-spacers.

Fluorescence polarization-based competition binding assay for c-Jun N-terminal kinases 1 and 2.

In order to evaluate the isoform selectivity of novel inhibitors within the c-Jun N-terminal kinase (JNK) family, a fluorescence polarization-based competition binding assay, previously developed for JNK3, was extended to the other isoforms JNK1 and JNK2. The assay is based on the displacement of a versatile fluorescent pyridinylimidazole-based probe and was validated by testing the precursor of the probe as well as standard JNK inhibitors.

Tri- and Tetrasubstituted Pyridinylimidazoles as Covalent Inhibitors of c-Jun N-Terminal Kinase 3.

The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to our well validated pyridinylimidazole scaffold varying several structural features in order to deduce crucial structure-activity relationships. Joint targeting of the hydrophobic region I and methylation of imidazole-N1 position increased the activity and reduced the number of off-targets. The most promising covalent inhibitor, the tetrasubstituted imidazole 3-acrylamido-N-(4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide (7) inhibits the JNK3 in the subnanomolar range (IC = 0.

Using Surface Scans for the Evaluation of Halogen Bonds toward the Side Chains of Aspartate, Asparagine, Glutamate, and Glutamine.

Using halogen-specific Connolly type molecular surfaces, we herein invented a new type of surface-based interaction analysis employed for the study of halogen bonding toward model systems of biologically relevant carboxylates (ASP/GLU) and carboxamides (ASN/GLN). Database mining and statistical assessment of the PDB revealed that such interactions are widely underrepresented at the moment. We observed important distance-dependent adaptions of the binding modes of halobenzenes from a preferential oxygen-directed to a bifurcated interaction geometry of the carboxylate.