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

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

Sk. Abdul Amin (Jadavpur University, Kolkata, India), Nilanjan Adhikari (Jadavpur University, Kolkata, India), Shovanlal Gayen (Dr. Harisingh Gour University, Sagar, India) and Tarun Jha (Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India)
DOI: 10.4018/IJQSPR.2018070101

Abstract

Human rhinoviruses (HRVs), a major cause of common cold and upper respiratory infections, may trigger severe respiratory complications like asthma and COPD. To date, no drugs are available in the market which are designed as novel HRV inhibitors despite the involvement of some pharmaceutical companies' due to economical and clinical constraints. HRV 3C protease may be a potential target for drug design as it plays crucial role in viral RNA replication and virion assembly process. Therefore, designing novel HRV 3Cpro inhibitors is necessary and demanding in the field of antiviral drug design. In this article, statistically significant and validated classification-based QSARs of a series of HRV 3Cpro inhibitors were performed for the first time as per the authors' knowledge. Results suggest that oxopyrrolidine and piperidinone rings are favored whereas carboxybenzyl and unsubstituted benzyl functions may be unfavorable. Moreover, this group, along with cyclic alkyl or aryl ring structures may favor HRV 3Cpro inhibition. These observations may be utilized for the design of a higher active anti-HRV agent in future.
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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 3Cpro) 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 3Cpro 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 3Cpro may be identified as a probable target for the treatment of HRV infections. The HRV 3Cpro, 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 3Cpro 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 3Cpro 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 3Cpro 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 3Cpro inhibitors that may be helpful in designing better inhibitors in future.

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