The success of approximate computational methods, such as molecular mechanics, or dispersion-corrected density functional theory, in the description of non-covalent interactions relies on accurate parameterizations. Benchmark data sets are thus required. This area is well developed for organic molecules and biomolecules but practically non-existent for boron clusters, which have been gaining in importance in modern drug as well as material design. To fill this gap, we have introduced two data sets featuring the most common non-covalent interaction of boron clusters, the dihydrogen bond, and calculated reference interaction energies at the "golden standard" CCSD(T)/CBS level. The boron clusters studied interact with formamide, methanol, water and methane at various distances and in two geometrical arrangements. The performance of the tested approximate methods is variable and recommendations for further use are given.

• Klíčová slova
• DFT-D3, carbaborane; CCSD(T), molecular mechanics, noncovalent interactions,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Malarial dipeptidyl aminopeptidases (DPAPs) are cysteine proteases important for parasite development thus making them attractive drug targets. In order to develop inhibitors specific to the parasite enzymes, it is necessary to map the determinants of substrate specificity of the parasite enzymes and its mammalian homologue cathepsin C (CatC). Here, we screened peptide-based libraries of substrates and covalent inhibitors to characterize the differences in specificity between parasite DPAPs and CatC, and used this information to develop highly selective DPAP1 and DPAP3 inhibitors. Interestingly, while the primary amino acid specificity of a protease is often used to develop potent inhibitors, we show that equally potent and highly specific inhibitors can be developed based on the sequences of nonoptimal peptide substrates. Finally, our homology modelling and docking studies provide potential structural explanations of the differences in specificity between DPAP1, DPAP3, and CatC, and between substrates and inhibitors in the case of DPAP3. Overall, this study illustrates that focusing the development of protease inhibitors solely on substrate specificity might overlook important structural features that can be exploited to develop highly potent and selective compounds.

• Klíčová slova
• dipeptidyl aminopeptidase, malaria, positional scanning, proteases, specificity,
• MeSH
• aminokyseliny chemie   MeSH
• dipeptidylpeptidasy a tripeptidylpeptidasy metabolismus   MeSH
• erytrocyty účinky léků   metabolismus   parazitologie   MeSH
• inhibitory proteas farmakologie   MeSH
• konformace proteinů MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• peptidové fragmenty metabolismus   MeSH
• Plasmodium falciparum účinky léků   růst a vývoj   metabolismus   MeSH
• substrátová specifita MeSH
• tropická malárie farmakoterapie   metabolismus   parazitologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aminokyseliny MeSH
• dipeptidyl peptidase III MeSH Prohlížeč
• dipeptidylpeptidasy a tripeptidylpeptidasy MeSH
• inhibitory proteas MeSH
• peptidové fragmenty MeSH