Frank M Boeckler

University of Tuebingen | EKU Tübingen · Division of Pharmaceutical and Medicinal Chemistry

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. First, we built an active compound set by collecting rep...

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, fragment...

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 1H,15N-HSQC NMR. We could...

Two new ircinianin-type sesterterpenoids, ircinianin lactone B and ircinianin lactone C (7 and 8), together with five known entities from the ircinianin compound family (1, 3–6) were isolated from the marine sponge Ircinia wistarii. Ircinianin lactones B and C (7 and 8) represent new ircinianin terpenoids with a modified oxidation pattern. Despite...

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...

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 p...

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 82.9% sequence identity and a 100% sequence identity for the binding s...

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 prol...

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-amastig...

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 con...

Halogen bonds have become increasingly popular interactions in molecular design and drug discovery. One of its 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.g., the C-X bo...

Halogen bonding (XB) as a modern molecular interaction has received increasing attention, not only in material 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...

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 man...

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 chem...

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 pa...

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 adaman...

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 pro...

The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to our well validated pyridinylimidazole scaffolds 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 act...

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 interacti...

• Many oncogenic mutants of the tumor suppressor p53 are conformationally unstable, including the frequently occurring Y220C mutant. We have previously developed several small-molecule stabilizers of this mutant. One of these molecules, PhiKan083, 1-(9‐ethyl‐9H‐carbazole‐3‐yl)-N-methylmethanamine, binds to a mutation-induced surface crevice with a...

Two fluorescein-labelled pyridinylimidazoles were synthesized and evaluated as probes for the binding affinity determination of potential kinase inhibitors to the c-Jun N-terminal kinase 3 (JNK3) and p38α mitogen-activated protein kinase (MAPK). Fluorescence polarization (FP)-based competition binding assays were developed for both enzymes using 1-...

The ubiquitous amide moiety of the protein backbone is an essential interaction partner in any binding site. Using quantum mechanical calculations, we evaluate how to target this moiety through halogen bonding. In contrast to previously employed atom-centric spherical scans, we make use of planar scans to additionally account for the delocalised π-...

Twelve derivatives of the general formula 3-substituted-6-chloroindoles were synthesized and tested for their growth inhibitory effects versus p53^+/+ colorectal cancer HCT116 and its p53 knockout isogenic cells; colorectal cancer cell p53^-/- SW480; the lung cancer cell line p53^-/- H1299; mouse embryonic fibroblasts...

The cyclization of oxidosqualene to lanosterol, catalyzed by the enzyme oxidosqualene cyclase (OSC), goes through a number of carbocationic high energy intermediates (HEI), and mimicking these intermediates is a promising approach for the development of OSC inhibitors. 3-Arylpiperidines (or tetrahydropyridines) were designed as steroidomimetic ring...

The destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states...

We target the gatekeeper MET146 of JNK3 to exemplify the applicability of X···S halogen bonds in molecular design using computational, synthetic, structural and biophysical techniques. In a designed series of aminopyrimidine-based inhibitors, we unexpectedly encounter a plateau of affinity. Compared to their QM-calculated interaction energies, part...

Recently, we have reported a systematic comparison of molecular preparation protocols (using MOE or Maestro) in combination with two docking tools (GOLD or Glide) employing our DEKOIS 2.0 benchmark sets. We herein demonstrate, how comparable settings of data preparation protocols can affect the profile and AUC of pROC-curves based on variations in...

Bioisosteric replacements are widely used in medicinal chemistry to improve physicochemical and ADME properties of molecules while retaining or improving affinity. Here, using the p53 cancer mutant Y220C as a test case, we investigate both computationally and experimentally whether an ethynyl moiety is a suitable bioisostere to replace iodine in li...

Despite its importance and all the considerable efforts made, the progress in drug discovery is limited. One main reason for this is the partly questionable data quality. Models relating biological activity and structures and in silico predictions rely on precisely and accurately measured binding data. However, these data vary so strongly, such tha...

Structure-based virtual screening techniques can help to identify new lead structures and complement other screening approaches in drug discovery. Prior to docking, the data (protein crystal structures and ligands) should be prepared with great attention to molecular and chemical details. Using a subset of 18 diverse targets from the recently intro...

We present a QM-derived empirical scoring function for the interaction between aromatic halogenated ligands and the carbonyl oxygen atom of the protein backbone. Applying this scoring function we developed an algorithm that evaluates the potential of protein-bound ligands to form favorable halogen bonding contacts upon scaffold decoration with chlo...

Halogen bonding has recently experienced a renaissance, gaining increased recognition as a useful molecular interaction in the life sciences. Halogen bonds are favorable, fairly directional interactions between an electropositive region on the halogen (the σ-hole) and a number of different nucleophilic interaction partners. Some aspects of halogen...

Author Summary Molecular dynamics simulations provide insight into the dynamic behavior of molecules, e.g., into the adopted spatial arrangements of its atoms over time. Methods differ in the approximations they employ, resulting in a trade-off between accuracy and speed that ranges from highly accurate but expensive quantum mechanical calculations...

The tumor suppressor p53 plays a central role in cancer defense. In approximately 50% of human cancers, it can be inactivated by mutation. Pharmacological chaperones have been proposed as a rescue strategy for mutants, such as Y220C, which lead to a decrease of the melting temperature of p53. By binding to the site where the mutation causes instab...

In this issue of Structure, Bista and colleagues report that inhibitors of the MDM2/p53 interaction can be designed to interact with a transiently folded α-helical segment of the MDM2 lid region. This suggests that targeting transient protein states in PPI inhibitor design could be a promising strategy to improve affinity and/or selectivity profile...

Halogen bonds are directional noncovalent interactions that can be used to target electron donors in a protein binding site. In this study, we employ quantum chemical calculations to explore halogen…nitrogen contacts involving histidine sidechains. We characterize the energetics on the MP2 level of theory using SCS-MP2 and CCSD(T)/CBS as reference...

Derivatives with scaffolds of 1,3,5-tri-substituted pyrazoline and 1,3,4,5-tetra-substituted pyrazoline were synthesized and tested for their inhibitory effects versus the p53(+/+) HCT116 and p53(-/-) H1299 human tumor cell lines. Several compounds were active against the two cell lines displaying IC50 values in the low micromolar range with a clea...

The tumour suppressor p53 plays a central role in cancer defense. In approximately 50% of human cancers, it can be inactivated by mutation. Pharmacological chaperones have been proposed as a rescue strategy for mutants, such as Y220C, which lead to a decrease of the melting temperature of p53. By binding to the site where the mutation causes insta...

A plethora of studies indicate that the development of multi-target drugs is beneficial for complex diseases like cancer. Accurate QSAR models for each of the desired targets assist the optimization of a lead candidate by the prediction of affinity profiles. Often, the targets of a multi-target drug are sufficiently similar such that, in principle,...

The application of molecular benchmarking sets helps to assess the actual performance of virtual screening (VS) workflows. To improve the efficiency of structure-based VS approaches, the selection and optimization of various parameters can be guided by benchmarking. With the DEKOIS 2.0 library, we aim to further extend and complement the collection...

p38α mitogen-activated protein (MAP) kinase is a main target in drug research concerning inflammatory diseases. Nevertheless, no inhibitor of p38α MAP kinase has been introduced to the market. This might be attributed to the fact that there is no inhibitor which combines outstanding activity in biological systems and selectivity. Herein an approach...

Halogen bonding has been known in material science for decades, but until recently, halogen bonds in protein-ligand interactions were largely the result of serendipitous discovery rather than rational design. In this perspective, we provide insights into the phenomenon of halogen bonding, with special focus on its role in drug discovery. We summari...

The proteins MDM2 and MDM4 are key negative regulators of the tumor suppressor protein p53, which are frequently upregulated in cancer cells. They inhibit the transactivation activity of p53 by binding separately or in concert to its transactivation domain. MDM2 is also a ubiquitin ligase that leads to the degradation of p53. Accordingly, MDM2 and...

Aggregation of destabilized mutants of the tumor suppressor p53 is a major route for its loss of activity. In order to assay drugs that inhibit aggregation of p53, we established the basic kinetics of aggregation of its core domain, using the mutant Y220C that has a mutation-induced, druggable cavity. Aggregation monitored by light scattering follo...

Halogen bonds are specific embodiments of the sigma hole bonding paradigm. They represent directional interactions between the halogens chlorine, bromine, or iodine and an electron donor as binding partner. Using quantum chemical calculations at the MP2 level, we systematically explore how they can be used in molecular design to address the omnipre...

The destabilizing p53 cancer mutation Y220C creates a druggable surface crevice. We developed a strategy exploiting halogen bonding for lead discovery to stabilize the mutant with small molecules. We designed halogen-enriched fragment libraries (HEFLibs) as starting points to complement classical approaches. From screening of HEFLibs and subsequent...

In the course of searching for new p38α MAP kinase inhibitors, we found that the regioisomeric switch from 3-(4-fluorophenyl)-4-(pyridin-4-yl)-1-(aryl)-1H-pyrazol-5-amine to 4-(4-fluorophenyl)-3-(pyridin-4-yl)-1-(aryl)-1H-pyrazol-5-amine led to an almost complete loss of p38α inhibition, but they showed activity against important cancer kinases. Am...

The dimeric mammalian phosphodiesterases (PDEs) are regulated by N-terminal domains. In PDE5, the GAF-A subdomain of a GAF-tandem (GAF-A and -B) binds the activator cGMP and in PDE10 GAF-B binds cAMP. GAF-tandem chimeras of PDE5 and 10 in which the 36 aa linker helix between GAF-A and -B was swapped lost allosteric regulation of a reporter adenylyl...

For widely applied in silico screening techniques success depends on the rational selection of an appropriate method. We herein present a fast, versatile, and robust method to construct demanding evaluation kits for objective in silico screening (DEKOIS). This automated process enables creating tailor-made decoy sets for any given sets of bioactive...

Halogen bonds are directional interactions involving an electron donor as binding partner. Employing quantum chemical calculations, we explore how they can be used in molecular design to address the sulfur atom in a methionine residue in a previously neglected, directed manner. We characterize energetics and directionality of these halogen bonds an...

New derivatives based upon the tetrahydro-β-carboline-hydantoin and tetrahydro-β-carboline-piperazinedione scaffolds were synthesized. All compounds were evaluated for their ability to inhibit PDE5 in vitro, and numerous compounds with IC(50) values in the low nanomolar range were identified including compounds derived from l-tryptophan. Compounds...

Halogen bonds are directional interactions involving an electron donor as binding partner. Employing quantum chemical calculations, we explore how they can be used in molecular design to address the sulfur atom in a methionine residue in a previously neglected, directed manner. We characterize energetics and directionality of these halogen bonds an...

The tumor suppressor p53 is mutationally inactivated in ≈50% of human cancers. Approximately one-third of the mutations lower the melting temperature of the protein, leading to its rapid denaturation. Small molecules that bind to those mutants and stabilize them could be effective anticancer drugs. The mutation Y220C, which occurs in ≈75,000 new ca...

The p53 tumor suppressor protein plays a critical role in eliminating potentially cancerous cells. When active, p53 inhibits cell cycle progression and promotes apoptosis, but when p53 is inactivated by mutation, the cell loses these critical defense pathways against cancer. Most oncogenic mutations in p53 occur in its DNA binding domain, and loss...

Various pharmacological studies have implicated the dopamine D(3) receptor as an interesting therapeutic target in the treatment of different neurological disorders. Because of these putative therapeutic applications, D(3) receptor ligands with diverse intrinsic activities have been an active field of research in recent years. Separation of purely...

Elucidation of the physiological role of the D3 receptor and its distribution in the brain using positron emission tomography (PET) is hampered by the lack of bioavailable subtype selective tracer ligands. To develop appropriate D3 radioligands, we designed an integrative procedure involving the elucidation of structural features determining D3 sel...

"Evolution consists largely of molecular tinkering."-Following the famous concept of the molecular geneticist and medicine Nobel laureate François Jacob, in this review we describe the structural evolution of dopamine D3 receptor ligands from the natural agonist dopamine (DA) to highly potent and subtype selective new agents by bioisosteric tinkeri...

Taking advantage of our in-house experimental data on dopamine D3 receptor modulators, we have successfully established highly significant CoMFA and CoMSIA models (q(cv)2 = 0.82/0.76). These models were carefully investigated to assure their stability and predictivity (r(pred)2 = 0.65/0.61) and subsequently applied to guide experimental investigati...

The development of privileged molecular scaffolds efficiently mimicking reverse turn motifs and thus increasing both binding and selectivity and enabling the elucidation of the bioactive conformation of a natural peptide has attracted remarkable interest. The frequent occurrence of proline in various turn patterns initiated the design of proline-ba...

The exploration of the chemical diversity space depends on the discovery of novel bioisosteric elements. As a continuation of our project on bilayered arene surrogates, we herein report on [2.2]paracyclophane-derived dopamine D3 receptor antagonists of type 4 and 6. For the most promising test compound 6a, bearing a 2-methoxyphenyl substituent, a s...

Seit der ersten Anwendung von L-DOPA an Parkinson-Patienten in den 1960er Jahren hat sich L-DOPA als “Goldstandard” für die Therapie von MP etabliert. Vor allem die im Laufe der Langzeittherapie auftretenden Dyskinesien und die verminderte Wirksamkeit limitieren die Anwendbarkeit von L-DOPA jedoch ganz erheblich. Im Bereich der Rezeptor-vermittelte...

Employing 1,3-dipolar cycloaddition for the synthesis of the 7a-azaindole nucleus, analogues of melatonin have been synthesized and tested against human and amphibian melatonin receptors. Introducing a phenyl substituent in position 2 of the heterocyclic moiety significantly increased binding affinity to both the MT1 and MT2 receptors. Shifting the...

Taking advantage of a 3D-QSAR based phar