Structural exploration of hydroxyethylamines as HIV-1 protease inhibitors: new features identified

Abstract

The current study deals with chemometric modelling strategies (Naïve Bayes classification, hologram-based quantitative structure–activity relationship (HQSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA)) to explore the important features of hydroxylamine derivatives for exerting potent human immunodeficiency virus-1 (HIV-1) protease inhibition. Depending on the statistically validated reliable and robust quantitative structure–activity relationship (QSAR) models, important and crucial structural features have been identified that may be responsible for enhancing the activity profile of these hydroxylamine compounds. Arylsulfonamide function along with methoxy or fluoro substitution is important for enhancing activity. Bulky steric substitution at the sulfonamide nitrogen disfavours activity whereas smaller hydrophobic substitution at the same position is found to be favourable. Apart from the crucial oxazolidinone moiety, pyrrolidine, cyclic urea and methyl ester functions are also responsible for increasing the HIV-1 protease inhibitory profile. Observations derived from these modelling studies may be utilized further in designing promising HIV-1 protease inhibitors of this class.

Keywords:

• HIV-1 protease
• hydroxylamine derivatives
• naïve Bayes classification
• HQSAR
• 3D-QSAR

Acknowledgments

NA is grateful to UGC, New Delhi for providing a Rajiv Gandhi National Fellowship. SG is thankful for the start-up grant from University Grants Commission (UGC), New Delhi (No. F.30-106/2015-BSR). TJ is thankful for the financial support from Universities with Potential for Excellence (UPE) Phase-II Program of UGC, New Delhi to Jadavpur University, Kolkata, India. The authors are grateful to the authority of Jadavpur University, India and Dr Harisingh Gour University, India for providing research facilities.