Structural comparison of diverse HIV-1 subtypes using molecular modelling and docking analyses of integrase inhibitors
Please always quote using this URN: urn:nbn:de:bvb:20-opus-211170
- 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 integraseThe 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.…
Author: | Darren Isaacs, Sello Given Mikasi, Adetayo Emmanuel Obasa, George Mondinde Ikomey, Sergey Shityakov, Ruben Cloete, Graeme Brendon Jacobs |
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URN: | urn:nbn:de:bvb:20-opus-211170 |
Document Type: | Journal article |
Faculties: | Fakultät für Biologie / Theodor-Boveri-Institut für Biowissenschaften |
Language: | English |
Parent Title (English): | Viruses |
ISSN: | 1999-4915 |
Year of Completion: | 2020 |
Volume: | 12 |
Issue: | 9 |
Article Number: | 936 |
Source: | Viruses (2020) 12:9, 936. https://doi.org/10.3390/v12090936 |
DOI: | https://doi.org/10.3390/v12090936 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | HIV-1; diversity; integrase; molecular docking; molecular modelling; naturally occurring polymorphisms |
Release Date: | 2023/05/24 |
Date of first Publication: | 2020/08/26 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |