TY  - JOUR
A1  - Isaacs, Darren
A1  - Mikasi, Sello Given
A1  - Obasa, Adetayo Emmanuel
A1  - Ikomey, George Mondinde
A1  - Shityakov, Sergey
A1  - Cloete, Ruben
A1  - Jacobs, Graeme Brendon
T1  - Structural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitors
JF  - Viruses
N2  - The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral integrase (IN) enzyme catalyzes integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of integrase strand transfer inhibitors (INSTIs). We applied computational methods of molecular modelling and docking to analyze the effect of NOPs on the full-length IN structure and INSTI binding. We identified 13 NOPs within the Cameroonian-derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any differences in INSTI binding affinity. However, linear regression analysis revealed a positive correlation between the Ki and EC50 values for DTG and BIC as strong inhibitors of HIV-1 IN subtypes. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment-naïve populations. This study supports the use of second-generation INSTIs such as DTG and BIC as part of first-line combination antiretroviral therapy (cART) regimens, due to a stronger genetic barrier to the emergence of drug resistance.
KW  - integrase
KW  - naturally occurring polymorphisms
KW  - HIV-1
KW  - molecular modelling
KW  - molecular docking
KW  - diversity
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211170
SN  - 1999-4915
VL  - 12
IS  - 9
ER  - 
TY  - JOUR
A1  - Wilhelms, Benedikt
A1  - Broscheit, Jens
A1  - Shityakov, Sergey
T1  - Chemical analysis and molecular modelling of cyclodextrin-formulated propofol and its sodium salt to improve drug solubility, stability and pharmacokinetics (cytogenotoxicity)
JF  - Pharmaceuticals
N2  - Propofol is a widely used general anesthetic in clinical practice, but its use is limited by its water-insoluble nature and associated pharmacokinetic and pharmacodynamic limitations. Therefore, researchers have been searching for alternative formulations to lipid emulsion to address the remaining side effects. In this study, novel formulations for propofol and its sodium salt Na-propofolat were designed and tested using the amphiphilic cyclodextrin (CD) derivative hydroxypropyl-β-cyclodextrin (HPβCD). The study found that spectroscopic and calorimetric measurements suggested complex formation between propofol/Na-propofolate and HPβCD, which was confirmed by the absence of an evaporation peak and different glass transition temperatures. Moreover, the formulated compounds showed no cytotoxicity and genotoxicity compared to the reference. The molecular modeling simulations based on molecular docking predicted a higher affinity for propofol/HPβCD than for Na-propofolate/HPβCD, as the former complex was more stable. This finding was further confirmed by high-performance liquid chromatography. In conclusion, the CD-based formulations of propofol and its sodium salt may be a promising option and a plausible alternative to conventional lipid emulsions.
KW  - propofol
KW  - anaesthesiology
KW  - HPβCD
KW  - \(^1\)H-NMR spectroscopy
KW  - calorimetry
KW  - molecular modelling
KW  - cytotoxicity
KW  - genotoxicity
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313705
SN  - 1424-8247
VL  - 16
IS  - 5
ER  -