György M. Keserű

Impact of Lipophilic Efficiency on Compound Quality

Lipophilic efficiency indices such as LLE and LELP were suggested to support balanced optimization of potency and ADMET profile. Here we investigated the performance of LLE and LELP on multiple data sets representing different stages of drug discovery including fragment and HTS hits and leads, development candidates, phase II compounds, and launched drugs. Analyzing their impact on ADME and safety properties and binding thermodynamics, we found that both LLE and LELP help identifying better quality compounds. LLE is sensible for the development stages but does not prefer fragment-type hits, while LELP has an advantage for this class of compounds and discriminates preferred starting points effectively. Both LLE and LELP have significant impact on ADME and safety profiles; however, LELP outperforms LLE in risk assessment at least on the present data set. On the basis of the results reported here, monitoring lipophilic efficiency metrics could contribute significantly to compound quality and might improve the output of medicinal chemistry programs.

Discovery of novel human histamine H4 receptor ligands by large-scale structure-based virtual screening

A structure-based virtual screening (SBVS) was conducted on a ligand-supported homology model of the human histamine H4 receptor (hH4R). More than 8.7 million 3D structures derived from different vendor databases were investigated by docking to the hH4R binding site using FlexX. A total of 255 selected compounds were tested by radioligand binding assay and 16 of them possessed significant [(3)H]histamine displacement. Several novel scaffolds were identified that can be used to develop selective H4 ligands in the future. As far as we know, this is the first SBVS reported on H4R, representing one of the largest virtual screens validated by the biological evaluation of the virtual hits.

Contributions of molecular properties to drug promiscuity.

In contrast to designed polypharmacology that can result in efficient drugs for complex disorders, unintended drug promiscuity has detrimental contribution to side effects and toxicology. Characterization of promiscuous compounds enhances the understanding of complex interaction patterns and aids the design of compounds with broader selectivity against off-targets that has a major impact on medicinal chemistry outcome. In this Miniperspective we provide insights to the effect of physicochemical parameters on promiscuity. Information collected from recent, large-scale in vitro studies enabled us to discuss the relationships between physicochemical properties and promiscuity in detail. In light of these data, lipophilicity and basic character have the highest influence. On the basis of the accumulated knowledge, we propose the extensive use of pre- and postsynthesis metrics, as well as strict control of physicochemical properties during medicinal chemistry optimizations.

In silico site of metabolism prediction of cytochrome P450-mediated biotransformations.

Introduction: Preclinical research involves the in vitro monitoring of metabolic stability to deliver compounds with improved ADME profiles. Prediction of the metabolically vulnerable points can substantially help in analyzing CYP-mediated metabolism data and support optimization efforts in drug discovery programs. Moreover, fast and reliable in silico predictions could accelerate the characterization of in vitro/in vivo metabolites. Areas covered: This paper reviews in silico methods available for CYP-mediated site of metabolism (SOM) prediction. Comprehensive and practical knowledge in this field can guide the identification of best practice and may inspire ideas for the development of novel approaches. Expert opinion: Comparison of the efficacy of SOM prediction methodologies revealed the general dependency on the studied isoform and substrate set. Increasing knowledge on P450 X-ray structures, on biotransformations and on the mechanistic details of the catalytic cycle revolutionized the prediction of SOM. Although no ultimate solution exits, combined methods covering both steric and electronic effects are preferred on most of the pharmaceutically relevant isoforms.

Recent developments on JAK2 inhibitors: a patent review

Importance of the field: JAK2 is one of the most promising targets against neoplastic growth. A somatic mutation (V617F) resulting in enhanced JAK2 kinase activity can be frequently found in patients with serious myeloproliferative neoplasms such as polycythemia vera, essential thrombocythemia and primary myelofibrosis. Preclinical results strongly support that JAK2 inhibitors could be effectively used in these indications. Pharmaceutical companies and academic groups have developed a number of potent JAK2 inhibitors during the last decade. Tolerability and effectiveness of the most promising compounds are currently being investigated in clinical trials. Areas covered in this review: In this paper, we aim to give a comprehensive review of the currently available patent literature of JAK2 inhibitors. What the reader will gain: We tried to collect the published core structures possessing JAK2 inhibitory potency including compounds developed by academic and industrial research groups. We review the currently available patent literature as well as the key papers containing additional information about the described JAK2 inhibitors. Clinical status data were collected by searching the Prous Integrity and Pharmaprojects databases. Take home message: The significant number of JAK2 inhibitors published and numerous clinical trials involving these compounds suggest that some of them might be approved in the next few years and can serve as novel drugs for the treatment of JAK2-dependent pathologies.

Identification of a novel inhibitor of JAK2 tyrosine kinase by structure-based virtual screening

Janus kinase 2 (JAK2) plays a crucial role in the pathomechanism of myeloproliferative disorders and hematologic malignancies. A somatic mutation of JAK2 (Val617Phe) was previously shown to occur in 98% of patients with polycythemia vera and 50% of patients with essential thrombocythemia and primary myelofibrosis. Thus, effective JAK2 kinase inhibitors may be of significant therapeutic importance. Here, we applied a structure-based virtual screen to identify novel JAK2 inhibitors. One JAK2 inhibitor in particular, G6, demonstrated remarkable potency as well as specificity, which makes it as a potential lead candidate against diseases related to elevated JAK2 tyrosine kinase activity.

Site of metabolism prediction on cytochrome P450 2C9: a knowledge-based docking approach

A novel structure-based approach for site of metabolism prediction has been developed. This knowledge-based method consists of three steps: (1) generation of possible metabolites, (2) docking the predicted metabolites to the CYP binding site and (3) selection of the most probable metabolites based on their complementarity to the binding site. As a proof of concept we evaluated our method by using MetabolExpert for metabolite generation and Glide for docking into the binding site of the CYP2C9 crystal structure. Our method could identify the correct metabolite among the three best-ranked compounds in 69% of the cases. The predictive power of our knowledge-based method was compared to that achieved by substrate docking and two alternative literature approaches.

Multiple Fragment Docking and Linking in Primary and Secondary Pockets of Dopamine Receptors

A sequential docking methodology was applied to computationally predict starting points for fragment linking using the human dopamine D3 receptor crystal structure and a human dopamine D2 receptor homology model. Two focused fragment libraries were docked in the primary and secondary binding sites, and best fragment combinations were enumerated. Similar top scoring fragments were found for the primary site, while secondary site fragments were predicted to convey selectivity. Three linked compounds were synthesized that had 9-, 39-, and 55-fold selectivity in favor of D3 and the subtype selectivity of the compounds was assessed on a structural basis.

The ability of 2-phosphabicyclo[2.2.2]oct-5-ene 2-oxides to undergo fragmentation of the bridging P-moiety

Abstract New 2-phosphabicyclo[2.2.2]octene 2-oxides (2 and 3) were synthesized by the Diels–Alder reaction of 1,2-dihydrophosphinine oxides (1) and dienophiles, such as N-phenyl maleimide and maleic anhydride. The X-ray structure of one of the products (2Ab) suggests that the phosphabicyclooctenes have a less strained framework than the phosphabicyclooctadienes described earlier. As a consequence of this, also confirmed by thermal examinations and semiempirical calculations, thermal fragmentation of the phosphabicyclooctenes requires more forcing conditions, than that of the bicyclooctadienes. The methylenephosphine oxide (10) ejected could be utilized in the phosphorylation of hydroquinone in moderate yield. Mass spectral fragmentation of cycloadducts 2 and 3 under electron-impact conditions seems to be in agreement with the preparative experiences.

Synthesis of the Spiro Derivatives of 1,2-Oxaphosphetes by [2+2] Cycloaddition of Cyclic 1-(2,4,6-Triisopropylphenyl)phosphine Oxides with Dimethyl Acetylenedicarboxylate†

Abstract Members of a new heterocyclic family, 1,2-oxaphosphetes were prepared by the unexpected [2+2] cycloaddition of the PO group of 1-(2,4,6-triisopropylphenyl) P-heterocycles with the acetylene moiety of dimethyl acetylenedicarboxylate. The new oxaphosphetes are spiro derivatives of the starting heterocycles and exhibit a phosphorus atom with trigonal bipyramidal geometry. PM3 semiempirical calculations justified the novel reaction path and suggested a stepwise reaction mechanism.