QM/MM Calculations Reveal the Different Nature of the Interaction of Two Carborane-Based Sulfamide Inhibitors of Human Carbonic Anhydrase II

The crystal structures of two novel carborane-sulfamide inhibitors in the complex with human carbonic anhydrase II (hCAII) have been studied using QM/MM calculations. Even though both complexes possess the strongly interacting sulfamide···zinc ion motif, the calculations have revealed the different nature of binding of the carborane parts of the inhibitors. The neutral <i>closo</i>-carborane cage was bound to hCAII mainly via dispersion interactions and formed only very weak dihydrogen bonds. On the contrary, the monoanionic <i>nido</i> cage interacted with the protein mainly via electrostatic interactions. It formed short and strong dihydrogen bonds (stabilization of up to 4.2 kcal/mol; H···H distances of 1.7 Å) with the polar hydrogen of protein NH₂ groups. This type of binding is unique among all of the classical organic and inorganic inhibitors of hCAII. Virtual glycine scanning allowed us to identify the amino-acid side chains, which made important contributions to ligand-binding energies. In summary, using QM/MM calculations, we have provided a detailed understanding of the differences between the interactions of two carborane sulfamides, identified the amino acids of hCAII with which they interact, and thus paved the way for the computer-aided rational design of selective boron-cluster-containing hCAII inhibitors

Structure-Aided Design of Novel Inhibitors of HIV Protease Based on a Benzodiazepine Scaffold

HIV protease is a primary target for the design of virostatics. Screening of libraries of non-peptide low molecular weight compounds led to the identification of several new compounds that inhibit HIV PR in the low micromolar range. X-ray structure of the complex of one of them, a dibenzo­[<i>b</i>,<i>e</i>]­[1,4]­diazepinone derivative, showed that two molecules of the inhibitor bind to the PR active site. Covalent linkage of two molecules of such a compound by a two-carbon linker led to a decrease of the inhibition constant of the resulting compound by 3 orders of magnitude. Molecular modeling shows that these dimeric inhibitors form two crucial hydrogen bonds to the catalytic aspartates that are responsible for their improved activity compared to the monomeric parental building blocks. Dibenzo­[<i>b</i>,<i>e</i>]­[1,4]­diazepinone analogues might represent a potential new class of HIV PIs

Synthesis, Structure–Activity Relationship Studies, and X-ray Crystallographic Analysis of Arylsulfonamides as Potent Carbonic Anhydrase Inhibitors

A series of arylsulfonamides has been synthesized and investigated for the inhibition of some selected human carbonic anhydrase isoforms. The studied compounds showed significant inhibitory effects in the nanomolar range toward druggable isoforms (hCA VII, hCA IX, and hCA XIV) (<i>K</i>_i values from 4.8 to 61.7 nM), whereas they generally exhibited significant selectivity over hCA I and hCA II, that are ubiquitous and considered off-target isoforms. On the basis of biochemical data, we herein discussed structure–affinity relationships for this series of arylsulfonamides, suggesting a key role for alkoxy substituents in CA inhibition. Furthermore, X-ray crystal structures of complexes of two active inhibitors (<b>I</b> and <b>2a</b>) with hCA II allowed us to elucidate the main interactions between the inhibitor and specific amino acid residues within the catalytic site

Fluidized Bed Incineration of Sewage Sludge in O₂/N₂ and O₂/CO₂ Atmospheres

Sewage sludge incineration in a fluidized bed is considered to be one of the most suitable ways of sewage sludge disposal. This process reduces the volume of the waste and causes the destruction of organic contaminants such as POPs, pharmaceuticals, and other compounds with endocrine-disrupting potential. Oxygen-enriched air combustion and oxy–fuel combustion can increase the combustion efficiency, reduce the amount of flue gas, and make possible CO₂ capture more effective. However, the influence of incineration medium composition has not yet been thoroughly investigated in the case of sewage sludge incineration. In this paper, the incineration of sewage sludge in a bubbling fluidized bed reactor was studied at oxygen-enriched air conditions, oxy–fuel conditions, and oxy–fuel conditions with zero and nonzero concentrations of steam, CO, NO, N₂O, and SO₂ in the inlet combustion medium. Consequently, the effects of various operating parameters on pollutants formation were comprehensively described with emphasis on aforementioned sewage sludge incineration processes. An increase in combustion temperature resulted in an increase in NO_<i>x</i> and SO₂ emissions and in a decrease in N₂O emissions. Increase in inlet oxygen concentration led to a decrease in NO_<i>x</i> and N₂O emissions. N₂O and SO₂ emissions were higher in CO₂-rich atmosphere (oxy–fuel combustion conditions). The presence of water vapor in the inlet combustion medium resulted mainly in the reduction of NO_<i>x</i> emissions. The presence of CO, NO, N₂O, and SO₂ in the dry inlet combustion medium reduced mainly overall nitrogen-to-NO_<i>x</i> conversion, while the effect on SO₂ removal efficiency was only marginal

Inorganic Polyhedral Metallacarborane Inhibitors of HIV Protease: A New Approach to Overcoming Antiviral Resistance

HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode

Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7‑Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists

Cyclic dinucleotides (CDNs) are second messengers that activate stimulator of interferon genes (STING). The cGAS-STING pathway plays a promising role in cancer immunotherapy. Here, we describe the synthesis of CDNs containing 7-substituted 7-deazapurine moiety. We used mouse cyclic GMP–AMP synthase and bacterial dinucleotide synthases for the enzymatic synthesis of CDNs. Alternatively, 7-(het)aryl 7-deazapurine CDNs were prepared by Suzuki–Miyaura cross-couplings. New CDNs were tested in biochemical and cell-based assays for their affinity to human STING. Eight CDNs showed better activity than 2′3′-cGAMP, the natural ligand of STING. The effect on cytokine and chemokine induction was also evaluated. The best activities were observed for CDNs bearing large aromatic substituents that point above the CDN molecule. We solved four X-ray structures of complexes of new CDNs with human STING. We observed π–π stacking interactions between the aromatic substituents and Tyr240 that are involved in the stabilization of CDN-STING complexes

Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7‑Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists

Cyclic dinucleotides (CDNs) are second messengers that activate stimulator of interferon genes (STING). The cGAS-STING pathway plays a promising role in cancer immunotherapy. Here, we describe the synthesis of CDNs containing 7-substituted 7-deazapurine moiety. We used mouse cyclic GMP–AMP synthase and bacterial dinucleotide synthases for the enzymatic synthesis of CDNs. Alternatively, 7-(het)aryl 7-deazapurine CDNs were prepared by Suzuki–Miyaura cross-couplings. New CDNs were tested in biochemical and cell-based assays for their affinity to human STING. Eight CDNs showed better activity than 2′3′-cGAMP, the natural ligand of STING. The effect on cytokine and chemokine induction was also evaluated. The best activities were observed for CDNs bearing large aromatic substituents that point above the CDN molecule. We solved four X-ray structures of complexes of new CDNs with human STING. We observed π–π stacking interactions between the aromatic substituents and Tyr240 that are involved in the stabilization of CDN-STING complexes

Structural Basis for Inhibition of Mycobacterial and Human Adenosine Kinase by 7‑Substituted 7‑(Het)aryl-7-deazaadenine Ribonucleosides

Adenosine kinase (ADK) from <i>Mycobacterium tuberculosis</i> (Mtb) was selected as a target for design of antimycobacterial nucleosides. Screening of 7-(het)­aryl-7-deazaadenine ribonucleosides with Mtb and human (<i>h</i>) ADKs and testing with wild-type and drug-resistant Mtb strains identified specific inhibitors of Mtb ADK with micromolar antimycobacterial activity and low cytotoxicity. X-ray structures of complexes of Mtb and <i>h</i>ADKs with 7-ethynyl-7-deazaadenosine showed differences in inhibitor interactions in the adenosine binding sites. 1D ¹H STD NMR experiments revealed that these inhibitors are readily accommodated into the ATP and adenosine binding sites of Mtb ADK, whereas they bind preferentially into the adenosine site of <i>h</i>ADK. Occupation of the Mtb ADK ATP site with inhibitors and formation of catalytically less competent semiopen conformation of MtbADK after inhibitor binding in the adenosine site explain the lack of phosphorylation of 7-substituted-7-deazaadenosines. Semiempirical quantum mechanical analysis confirmed different affinity of nucleosides for the Mtb ADK adenosine and ATP sites