8 research outputs found
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 NH<sub>2</sub> 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
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><sub>i</sub> 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
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
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
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 <sup>1</sup>H 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