We have developed a fast and robust computational method for prediction of antiviral activity in automated de novo design of HIV-1 reverse transcriptase inhibitors. This is a structure-based approach that uses a linear relation between activity and interaction energy with discrete orientation sampling and with localized interaction energy terms. The localization allows for the analysis of mutations of the protein target and for the separation of inhibition and a specific binding to the enzyme. We apply the method to the prediction of pIC(50) of HIV-1 reverse transcriptase inhibitors. The model predicts the activity of an arbitrary compound with a q(2) of 0.681 and an average absolute error of 0.66 log value, and it is fast enough to be used in high-throughput computational applications.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/jm049534r | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Prevalence of drug resistance mutations in low-level viremia patients under antiretroviral therapy in Southwestern China: a cross-sectional study.
J Antimicrob Chemother
January 2025
Department of Laboratory Medicine, Yunnan Provincial Infectious Disease Hospital, Kunming 650301, China.
Objectives: This study aimed to evaluate the prevalence and characteristics of drug resistance mutations (DRMs) in patients with low-level viremia (LLV) in Southwestern China, as it has become a growing challenge in AIDS clinical practice.
Methods: This cross-sectional study was performed in Yunnan Province, Southwestern China. LLV was defined as 50-999 copies/mL of plasma viral load with antiretroviral therapy (ART) for at least 6 months.
Unlabelled: The HIV-1 Rev-RRE regulatory axis plays a crucial role in viral replication by facilitating the nucleo-cytoplasmic export and expression of viral mRNAs with retained introns. In this study, we investigated the impact of variation in Rev-RRE functional activity on HIV-1 replication kinetics and reactivation from latency. Using a novel HIV-1 clone with an interchangeable Rev cassette, we engineered viruses with different Rev functional activities and demonstrated that higher Rev-RRE activity confers greater viral replication capacity while maintaining a constant level of Nef expression.
View Article and Find Full Text PDFReactivation of latent HIV-1 by the glucocorticoid receptor modulator AZD9567.
J Virol
January 2025
Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany.
One key determinant of HIV-1 latency reversal is the activation of the viral long terminal repeat (LTR) by cellular transcription factors such as NF-κB and AP-1. Interestingly, the activity of these two transcription factors can be modulated by glucocorticoid receptors (GRs). Furthermore, the HIV-1 genome contains multiple binding sites for GRs.
View Article and Find Full Text PDFResistance mutations that distinguish HIV-1 envelopes with discordant VRC01 phenotypes from multi-lineage infections in the HVTN703/HPTN081 trial: implications for cross-resistance.
J Virol
January 2025
SA MRC Antibody Immunity Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg, South Africa.
The Antibody Mediated Prevention (AMP) trials showed that passively infused VRC01, a broadly neutralizing antibody (bNAb) targeting the CD4 binding site (CD4bs) on the HIV-1 envelope protein (Env), protected against neutralization-sensitive viruses. We identified six individuals from the VRC01 treatment arm with multi-lineage breakthrough HIV-1 infections from HVTN703, where one variant was sensitive to VRC01 (IC < 25 ug/mL) but another was resistant. By comparing Env sequences of resistant and sensitive clones from each participant, we identified sites predicted to affect VRC01 neutralization and assessed the effect of their reversion in the VRC01-resistant clone on neutralization sensitivity.
View Article and Find Full Text PDFPrevalence of major INSTI and HIV-1 drug resistance mutations in pre- and antiretroviral-treated patients in Indonesia.
Narra J
December 2024
Department of Clinical Pathology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
Indonesia has one of the highest HIV infection rates in Southeast Asia. The use of dolutegravir, an integrase strand transfer inhibitor (INSTI), as a first-line treatment underscores the need for detailed data on INSTI drug resistance mutations (DRMs). Currently, there is a lack of comprehensive data on DRMs INSTI and other HIV drug resistance in Indonesian patients, both pre- and post-treatment.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!