title: An in-silico approach aimed to clarify the role of Y181C and K103N HIV-1 reverse transcriptase mutations versus Indole Aryl Sulphones.
abstract: 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.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale A, Avogadro Largo Donegani 2, 28100 Novara, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Massarotti
authors.affiliation: Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy. Electronic address: antonio.coluccia@uniroma1.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Coluccia
mesh_terms: D020134:Catalytic Domain; D024882:Drug Resistance, Viral / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D015497:HIV-1 / Q000737:chemistry* / Q000201:enzymology; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000737:chemistry*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009570:Nitriles; D025341:Principal Component Analysis; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011724:Pyridazines / Q000737:chemistry*; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D007211:Indoles; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D013450:Sulfones; C451734:etravirine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: Drug resistant reverse transcriptase; Molecular dynamics; Non nucleoside reverse transcriptase inhibitors