Aurachin RE (1) is a strong antibiotic that
was recently
found to possess 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA)
and bacterial electron transport inhibitory activities. Aurachin RE
is the only molecule in a series of aurachin natural products that
has the chiral center in the alkyl side chain at C9′-position.
To identify selective MenA inhibitors against Mycobacterium
tuberculosis, a series of chiral molecules were designed
based on the structures of previously identified MenA inhibitors and 1. The synthesized molecules were evaluated in in vitro assays,
including MenA enzyme and bacterial growth inhibitory assays. We could
identify novel MenA inhibitors that showed significant increase in
potency of killing nonreplicating M. tuberculosis in the low oxygen recovery assay (LORA) without inhibiting other
Gram-positive bacterial growth even at high concentrations. The MenA
inhibitors reported here are useful new pharmacophores for the development
of selective antimycobacterial agents with strong activity against
nonreplicating M. tuberculosis.
We report the effect of the natural polyphenolic compounds from green tea on the catalytic activity of Ribonuclease A (RNase A). The compounds behave as noncompetitive inhibitors of the protein with inhibition constants ranging from 80-1300 microM. The dissociation constants range from 50-150 microM for the RNase A-polyphenol complexes as determined by ultraviolet (UV) and circular dichroism (CD) studies. We have also investigated the changes in the secondary structure of RNase A on complex formation by CD and Fourier transformed infrared (FTIR) spectroscopy. The presence of the gallate moiety has been shown to be important for the inhibition of enzymatic activity. Docking studies for these compounds indicate that the preferred site of binding is the region encompassing residues 34-39 with possible hydrogen bonding with Lys 7 and Arg 10. Finally we have also looked at changes in the accessible surface area of the interacting residues on complex formation for an insight into the residues involved in the interaction.
Ribonuclease A (RNase A) serves as a convenient model enzyme in the identification and development of inhibitors of proteins that are members of the ribonuclease superfamily. This is principally because the biological activity of these proteins, such as angiogenin, is linked to their catalytic ribonucleolytic activity. In an attempt to inhibit the biological activity of angiogenin, which involves new blood vessel formation, we employed different dinucleosides with varied non-natural backbones. These compounds were synthesized by coupling aminonucleosides with dicarboxylic acids and amino- and carboxynucleosides with an amino acid. These molecules show competitive inhibition with inhibition constant (K(i)) values of (59±3) and (155±5) μM for RNase A. The compounds were also found to inhibit angiogenin in a competitive fashion with corresponding K(i) values in the micromolar range. The presence of an additional polar group attached to the backbone of dinucleosides was found to be responsible for the tight binding with both proteins. The specificity of different ribonucleolytic subsites were found to be altered because of the incorporation of a non-natural backbone in between the two nucleosidic moieties. In spite of the replacement of the phosphate group by non-natural linkers, these molecules were found to selectively interact with the ribonucleolytic site residues of angiogenin, whereas the cell binding site and nuclear translocation site residues remain unperturbed. Docked conformations of the synthesized compounds with RNase A and angiogenin suggest a binding preference for the thymine-adenine pair over the thymine-thymine pair.
In this study we have generated a pharmacophore model of triple uptake
inhibitor compounds based on novel asymmetric pyran derivatives and the newly
developed asymmetric furan derivatives. The model revealed features important
for inhibitors to exhibit a balanced activity against dopamine transporter
(DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). In
particular, a ‘folded’ conformation was found common to the
active pyran compounds in the training set and was crucial to triple uptake
inhibitory activity. Furthermore, the distances between the benzhydryl moiety
and the N-benzyl group as well as the orientation of the
secondary nitrogen were also important for TUI activity. We have validated our
findings by synthesizing and testing novel asymmetric pyran analogs. The present
work has also resulted in the discovery of a new series of asymmetric
tetrahydrofuran derivatives as novel TUIs. Lead compounds 41 and
42 exhibited moderate TUI activity. Interestingly, the highest
TUI activity by lead tetrahydrofuran compounds e.g. 41 and
42, was exhibited in a stereochemical preference similar to
pyran TUI e.g. D-161.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.