First Report on the Validated Classification-Based Chemometric Modeling of Human Rhinovirus 3C Protease (HRV 3Cpro) Inhibitors

Introduction

Human rhinoviruses (HRVs), belonging to the family of picornavirus, play a significant role in causing common cold and upper respiratory infections that has a great impact on the health and economy worldwide (Simasek & Blandino, 2007; DePlama, Vliegen, DeClercg & Neyts, 2008; Jensen, Walker, Jans & Ghildyal, 2015; Kawatkar et al., 2016). Although the infection is generally mild and self-limiting, HRV infection may precipitate severe respiratory complications such as asthma exacerbations and chronic obstructive pulmonary disease (COPD) (Message et al., 2008; Denlinger et al., 2011; O’Bryne, 2011; Baxter et al., 2011). Therefore, it may be assumed that prevention and early treatment against the HRV infections may impart some beneficial effects (Gwaltney, Winther, Patrie & Hendly, 2002; Kawatkar et al., 2016). In the United States alone, an estimated cost related to the cold surpassed $40 billion during 2003 (Schuneman et al., 2014). Therefore, major challenges and interests are lying in the discovery process of anti-HRV drugs by pharmaceutical industries (Binford et al., 2005). Till date, no approved drug candidates of HRV infections are available in the market despite the higher clinical significance (DePlama, Vliegen, DeClercg & Neyts, 2008; Kawatkar et al., 2016). However, vaccination may be a useful strategy in eradicating HRV infection, but it is not feasible due to the presence of more than 100 distinct HRV serotypes and their cross-reactions (Jensen, Walker, Jans & Ghildyal, 2015). Therefore, targeting the viral proteins or limiting their interference with the host proteins by small molecule inhibitors may be a valuable strategy to reduce the infection rate. Recently, HRV 3C protease (HRV 3C^pro) and capsid-forming viral proteins have emerged out as potential therapeutic targets (Kawatkar et al., 2016). During viral RNA replication and assembling the virion, HRV 3C^pro is found to play a crucial role in the cleavage of the viral polypeptide into functionally and structurally essential proteins generated from the translational processes by viral RNA genome (Rotbart, 2000; DePlama, Vliegen, DeClercg & Neyts, 2008; Baxter et al., 2011). Therefore, HRV 3C^pro may be identified as a probable target for the treatment of HRV infections. The HRV 3C^pro, a cysteine protease, possesses structural similarity with the trypsin protein superfamily but shows less homology to the mammalian enzymes (Matthews et al., 1994; Allaire, Chernaia, Malcolm, & James, 1994; Reich et al., 2000; DePlama, Vliegen, DeClercg & Neyts, 2008). Due to the importance of HRV 3C^pro in the viral replication process, it is identified as a unique target for the development of potential anti-rhinoviral drugs (Wang, 1998; Dragovich, 2001). Rupintrivir, a potent reversible HRV 3C^pro inhibitor, exhibited good response against viral infection with acceptable safety and lower toxic profile (Patick et al., 1999; Hayden et al., 2003; Hsyu, Pithavala, Gersten, Penning, & Kerr, 2002; Kawatkar et al., 2016) but failed to show clinical significance (Patick et al., 2005). Despite knowing the binding mode of such type of inhibitors along with the crystal structures, no drugs are identified till now. Therefore, designing potential and novel inhibitors of HRV 3C^pro is still demanding in the field of antiviral drug design. In this article, we have attempted developing, for the first time, validated classification-based QSARs of a series of HRV 3C^pro inhibitors that may be helpful in designing better inhibitors in future.