Massarotti Alberto, Coluccia Antonio
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale A, Avogadro Largo Donegani 2, 28100 Novara, Italy.
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.
J Mol Graph Model. 2016 Jan;63:49-56. doi: 10.1016/j.jmgm.2015.11.013. Epub 2015 Nov 25.
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.
HIV-1耐药毒株的出现仍然是药物研发的关键关注点。非核苷类逆转录酶抑制剂已被证明对HIV-1野生型非常有效，但除了二芳基嘧啶类（如依曲韦林，1）之外，对突变的逆转录酶具有高水平耐药性。通过计算方法研究了两种临床上最相关的逆转录酶突变（Y181C；K103N）的影响。这涉及分子动力学、主成分分析（PCA）和残基相互作用网络（RINs）。该方法应用于化合物1以及吲哚基芳基砜类（IASs 2和3），这是一类对突变的逆转录酶形式也有活性的强效逆转录酶抑制剂。这项研究的分子见解与所研究突变的耐药机制相一致，可能有助于设计对耐药菌株具有高配体效力的新型逆转录酶抑制剂。
