An in-silico approach aimed to clarify the role of Y181C and K103N HIV-1 reverse transcriptase mutations versus Indole Aryl Sulphones

• Molecular dynamics simulation was carried out to study the effects of Y181C and K103N reverse transcriptase mutations on DAPYs and IASs binding mode.
• Trajectories analysis confirmed the crucial role of inhibitors flexibility to retain fruitful binding modes versus mutated RT.
• IASs binding plasticity sounds to be peculiar.

The emergence of HIV-1 drugs resistant stains remains of pivotal interest in relation to drugs development. Non nucleoside reverse transcriptase inhibitors proven to be very effective versus HIV-1 wild type but, with the only exception of diarylpyrimidines (e.g., etravirine, 1), were featured by high-level resistance versus mutated RT.The effects of two of the most clinically relevant RT mutations (Y181C; K103N) were studied by a computational approach. This involved molecular dynamics, principal components analysis (PCA) and residue interactions networks (RINs). The methodology was applied to 1 and to Indolyl Aryl Sulphones (IASs 2 and 3), a class of potent RT inhibitors active also versus mutated RT forms. The molecular insight from this study was in accordance with the proposed mechanism of resistance for studied mutations and it might be useful in the design of novel RT inhibitors with high ligand efficacy on resistant strains.

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