In this paper, we studied a designed series of aldose reductase (AR) inhibitors. The series was derived from a known AR binder, which had previously been shown to form a halogen bond between its bromine atom and the oxygen atom of the Thr-113 side chain of AR. In the series, the strength of the halogen bond was modulated by two factors, namely bromine-iodine substitution and the fluorination of the aromatic ring in several positions. The role of the single halogen bond in AR-ligand binding was elucidated by advanced binding free energy calculations involving the semiempirical quantum chemical Hamiltonian. The results were complemented with ultrahigh-resolution X-ray crystallography and IC50 measurements. All of the AR inhibitors studied were shown by X-ray crystallography to bind in an identical manner. Further, it was demonstrated that it was possible to decrease the IC50 value by about 1 order of magnitude by tuning the strength of the halogen bond by a monoatomic substitution. The calculations revealed that the protein-ligand interaction energy increased upon the substitution of iodine for bromine or upon the addition of electron-withdrawing fluorine atoms to the ring. However, the effect on the binding affinity was found to be more complex due to the change of the solvation/desolvation properties within the ligand series. The study shows that it is possible to modulate the strength of a halogen bond in a protein-ligand complex as was designed based on the previous studies of low-molecular-weight complexes.
- MeSH
- aldehydreduktasa antagonisté a inhibitory chemie MeSH
- halogeny chemie MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory enzymů chemie MeSH
- krystalografie rentgenová MeSH
- molekulární modely MeSH
- počítačová simulace MeSH
- vodíková vazba MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Metallacarborane moieties have been identified as promising pharmacophores. The pharmaceutical use of such compounds is, however, complicated by their low solubility and tendency to self-assemble in aqueous solution. In this work, we estimated the solubilities of a vast series of metallacarboranes [cobalt bis(dicarbollide) derivatives] in pure water, saline, and saline with human serum albumin as a model of blood plasma. In addition, we determined the octanol-water partition coefficients (Pow) as a lipophilicity descriptor. Pow weakly correlates with the water solubility of metallacarboranes, whereas the ability of HSA to increase the solubility of metallacarboranes correlates well with their Pow values. Because metallacarboranes are known inhibitors of HIV protease, the possible correlation between Pow and the ability to inhibit HIV protease was investigated. Results from this study indicate that interaction of metallacarborane inhibitors with HIV protease is driven by specific binding rather than by promiscuous lipophilic interactions. The most promising candidates for further drug development were identified by ligand lipophilicity efficiency analysis.
- MeSH
- inhibitory HIV-proteasy chemie farmakologie MeSH
- kobalt chemie farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- lipidy chemie MeSH
- molekulární struktura MeSH
- objevování léků MeSH
- organokovové sloučeniny chemie farmakologie MeSH
- rozpustnost MeSH
- sérový albumin chemie MeSH
- sloučeniny boru chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cobalt bis(dicarbollide) derivatives are promising therapeutic agents however their utilization is complicated due to their low solubility and self-assembling in water. Earlier we have shown that their solubility can be increased by using of suitable biocompatible excipients--carriers of pharmaceutically active compounds. Expected mechanism of solubilization was disassembling of self-assemblies and complexation of unimers. Newly our results of time-dependent light scattering study correct this presumption. Poor solubility of all derivatives can be easily improved by using various excipients, however only heptakis(2,6-di-O-methyl)-β-cyclodextrin displays ability to disassemble self-assemblies of all derivatives and suppress their self-assembling. Surprisingly, the other excipients participate on formation of mixed assemblies of derivative/excipient complex or cover assemblies to make them more soluble without decreasing their size.
- MeSH
- biologická dostupnost MeSH
- hydrodynamika MeSH
- kobalt chemie MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- organokovové sloučeniny chemie farmakokinetika MeSH
- radiační rozptyl MeSH
- rozpustnost MeSH
- světlo MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We report the first evidence that boron-containing nucleoside conjugates have a tendency to associate in water solutions. The size, charge, and exoskeletal pattern of the boron cluster can strongly influence the aggregation. The aggregation of nucleosides with attached boron clusters was observed using light scattering and atomic force microscopy techniques. Although the species containing either the bulky amphiphilic [3-cobalt(III) bis(1,2-dicarbollide)]- anion or the electroneutral dicarba-closo-dodecaboranyl moiety tend to form stable nanoparticles in aqueous solutions, the compounds bearing the smaller, negatively charged dicarba-nido-undecaboranyl moiety as well as the unmodified nucleosides do not aggregate. The light scattering measurements also showed that the aggregated species can interact with nonionic surfactant Triton X-100 in solution. The partition coefficients P in the water-octanol system correlate fairly well with the aggregation tendency observed by light scattering measurements. This finding allows us to predict the association behavior of boron-cluster-containing nucleosides on a qualitative level. The observed phenomenon can contribute to a better understanding of biological properties of boronated nucleosides and the design of boronated nucleoside-based drugs such as boron carriers for boron neutron capture therapy of tumors (BNCT) and antiviral agents.
Tetraphenylporphyrin conjugates with one (PB1) and four (PB4) cobalt(III) bis(1,2-dicarbollide) substituents were synthesized and the physicochemical and photophysical properties as well as inhibition of HIV-1 protease were described. In methanol, both PB1 and PB4 were monomeric producing the triplet states and singlet oxygen after excitation. The triplet states of PB4 were quickly protonated. Porphyrins exhibited a small decrease of the quantum yields of the singlet oxygen formation (17% for PB4 and 13% for PB1) as compared with 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin. On the contrary, no singlet oxygen was detected in aqueous solutions because of strong aggregation. Light scattering and atomic force microscopy (AFM) measurements documented that the behavior of aggregates in aqueous solutions is fairly complex and depends on pH, concentration, and aging. The aggregation started from spherical particles in neutral solutions. In acidic solutions, extended aggregation occurred because of slow protonation of the porphyrin pyrrole nitrogen atoms. Both PB1 and PB4 are new representatives of nonpeptide HIV-1 protease inhibitors. Their activity increased with the increasing number of the cobalt(III) bis(1,2-dicarbollide) substituents and was characterized with the IC50 values of 290+/-44 nM for PB1 and 77+/-13 nM for PB4.
- MeSH
- financování organizované MeSH
- HIV-proteasa metabolismus MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory HIV-proteasy farmakologie chemie MeSH
- kyslík chemie MeSH
- mikroskopie atomárních sil MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- organokovové sloučeniny chemie MeSH
- porfyriny farmakologie chemie MeSH
- sloučeniny boru chemie MeSH
- substrátová specifita MeSH
