Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study

Background

Novel pentacycloundecane (PCU)-lactone-CO-EAIS peptide inhibitors were designed, synthesized, and evaluated against wild-type C-South African (C-SA) HIV-1 protease. Three compounds are reported herein, two of which displayed IC₅₀ values of less than 1.00 μM. A comparative MM-PB(GB)SA binding free energy of solvation values of PCU-lactam and lactone models and their enantiomers as well as the PCU-lactam-NH-EAIS and lactone-CO-EAIS peptide inhibitors and their corresponding diastereomers complexed with South African HIV protease (C-SA) was performed. This will enable us to rationalize the considerable difference between inhibitory concentration (IC₅₀) of PCU-lactam-NH-EAIS and PCU-lactone-CO-EAIS peptides.

Results

The PCU-lactam model exhibited more negative calculated binding free energies of solvation than the PCU-lactone model. The same trend was observed for the PCU-peptide inhibitors, which correspond to the experimental activities for the PCU-lactam-NH-EAIS peptide (IC₅₀ = 0.076 μM) and the PCU-lactone-CO-EAIS peptide inhibitors (IC₅₀ = 0.850 μM). Furthermore, a density functional theory (DFT) study on the natural atomic charges of the nitrogen and oxygen atoms of the three PCU-lactam, PCU-lactim and PCU-lactone models were performed using natural bond orbital (NBO) analysis. Electrostatic potential maps were also used to visualize the electron density around electron-rich regions. The asymmetry parameter (η) and quadrupole coupling constant (χ) values of the nitrogen and oxygen nuclei of the model compounds were calculated at the same level of theory. Electronic molecular properties including polarizability and electric dipole moments were also calculated and compared. The Gibbs theoretical free solvation energies of solvation (∆G_solv) were also considered.

Conclusions

A general trend is observed that the lactam species appears to have a larger negative charge distribution around the heteroatoms, larger quadrupole constant, dipole moment and better solvation energy, in comparison to the PCU-lactone model. It can be argued that these characteristics will ensure better eletronic interaction between the lactam and the receptor, corresponding to the observed HIV protease activities in terms of experimental IC₅₀ data.

Electronic supplementary material

The online version of this article (doi:10.1186/s12929-015-0115-5) contains supplementary material, which is available to authorized users.     

<Emphasis Type="Italic">Kuth</Emphasis> (<Emphasis Type="Italic">Saussurea lappa</Emphasis>) cultivation in the cold desert environment of the Lahaul valley,northwestern Himalaya,India: arising threats and need to revive socio-economic values

Surveys were conducted in the cold desert environment of the Lahaul valley in the northwestern Himalaya for assessing the past and present status of Kuth (Saussurea lappa) cultivation. The findings reveal that this age-old practice now is in bottleneck. Main factors responsible for this setback to the species were the lengthy cultivation cycle, small land holdings, and even fluctuating and relatively low market prices. Owing to these constraints farmers have now started replacing cultivation of this threatened herb with pea (Pisum sativum L.), potato (Solanum tuberosum L.) and hop (Humulus lupulus L.). These crops obtained popularity due to comparatively more economic returns as well as their easy adaptability to the short growth season of the cold desert environment. Kuth cultivation in this region is among the interesting examples of domesticating wild medicinal herb by some innovative farmers during the 1920s. However, in the recent past farmers have been less interested to continue this practice due to its larger cultivation cycle, more profits with cash crops like pea and potato, and permit formalities at the time of export from the valley. In addition to being the oldest cash crop in the cold desert environment, Kuth is an endangered medicinal herb that has to be conserved on a priority basis. This study attempts to find out potential measures such as regular revision of market rates, development of existing uncultivable land under medicinal plant cultivation and strengthening the marketing network through establishment of federations of farmers at village level to revive cultivation of this important species.     

GEOGRAPHICAL VARIATION IN THE RATE OF EVOLUTION: EFFECT OF AVAILABLE ENERGY OR FLUCTUATING ENVIRONMENT?

In a recent paper, Wright et al. (2003) argue for the hypothesis that greater biologically available energy elevates the rate of molecular evolution. However, their results are also consistent with alternative hypotheses that invoke either environmentally driven variation in effective population sizes, or natural selection, or both. The available energy gradient cited by Wright et al. is linearly correlated with temperature fluctuations, and the observed rate heterogeneity could be a consequence of this environmental variability. The distribution of phylogenetic branch lengths alone is insufficient to distinguish between the hypotheses, and complementary approaches are suggested.     

Glycosyl trichloroacetylcarbamate: a new glycosyl donor for O-glycosylation

Glycosyl trichloroacetylcarbamates, readily obtained by reacting 1-hydroxy sugars with trichloroacetylisocyanate, have been found as excellent glycosyl donors, and the corresponding O-glycosides are formed in good to excellent yields with a fairly good degree of selectivity.     

Fluid shear regulates the kinetics and receptor specificity of Staphylococcus aureus binding to activated platelets

The interaction between surface components on the invading pathogen and host cells such as platelets plays a key role in the regulation of endovascular infections. However, the mechanisms mediating Staphylococcus aureus binding to platelets under shear remain largely unknown. This study was designed to investigate the kinetics and molecular requirements of platelet-S. aureus interactions in bulk suspensions subjected to a uniform shear field. Hydrodynamic shear-induced collisions augment platelet-S. aureus binding, which is further potentiated by platelet activation with stromal derived factor-1beta. Peak adhesion efficiency occurs at low shear (100 s(-1)) and decreases with increasing shear. The molecular interaction of platelet alpha(IIb)beta(3) with bacterial clumping factor A through fibrinogen bridging is necessary for stable bacterial binding to activated platelets under shear. Although this pathway is sufficient at low shear (相似文献   

Effect of formulation factors on in vitro permeation of moxifloxacin from aqueous drops through excised goat, sheep, and buffalo corneas

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V-ATPase V1 sector is required for corpse clearance and neurotransmission in Caenorhabditis elegans

The vacuolar-type ATPase (V-ATPase) is a proton pump composed of two sectors, the cytoplasmic V(1) sector that catalyzes ATP hydrolysis and the transmembrane V(o) sector responsible for proton translocation. The transmembrane V(o) complex directs the complex to different membranes, but also has been proposed to have roles independent of the V(1) sector. However, the roles of the V(1) sector have not been well characterized. In the nematode Caenorhabditis elegans there are two V(1) B-subunit genes; one of them, vha-12, is on the X chromosome, whereas spe-5 is on an autosome. vha-12 is broadly expressed in adults, and homozygotes for a weak allele in vha-12 are viable but are uncoordinated due to decreased neurotransmission. Analysis of a null mutation demonstrates that vha-12 is not required for oogenesis or spermatogenesis in the adult germ line, but it is required maternally for early embryonic development. Zygotic expression begins during embryonic morphogenesis, and homozygous null mutants arrest at the twofold stage. These mutant embryos exhibit a defect in the clearance of apoptotic cell corpses in vha-12 null mutants. These observations indicate that the V(1) sector, in addition to the V(o) sector, is required in exocytic and endocytic pathways.     

Human MECP2 gene at Q28 arm of X chromosome as a suitable target for monitoring PCR inhibition in a nested, multiplexed HIV-1 DNA detection protocol

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