Two Birds with One Stone? Possible Dual-Targeting H1N1 Inhibitors from Traditional Chinese Medicine

Abstract

The H1N1 influenza pandemic of 2009 has claimed over 18,000 lives. During this pandemic, development of drug resistance further complicated efforts to control and treat the widespread illness. This research utilizes traditional Chinese medicine Database@Taiwan (TCM Database@Taiwan) to screen for compounds that simultaneously target H1 and N1 to overcome current difficulties with virus mutations. The top three candidates were de novo derivatives of xylopine and rosmaricine. Bioactivity of the de novo derivatives against N1 were validated by multiple machine learning prediction models. Ability of the de novo compounds to maintain CoMFA/CoMSIA contour and form key interactions implied bioactivity within H1 as well. Addition of a pyridinium fragment was critical to form stable interactions in H1 and N1 as supported by molecular dynamics (MD) simulation. Results from MD, hydrophobic interactions, and torsion angles are consistent and support the findings of docking. Multiple anchors and lack of binding to residues prone to mutation suggest that the TCM de novo derivatives may be resistant to drug resistance and are advantageous over conventional H1N1 treatments such as oseltamivir. These results suggest that the TCM de novo derivatives may be suitable candidates of dual-targeting drugs for influenza.

Beware of docking!

“…In our experience, translating drug discovery from CADD to clinical trials is difficult. For example, some top potent hits screened by docking from the TCM database failed in the final bioactivity test [20,[22][23][24][25][26][27]. However, if a hit comes first from a bioassay -for example, if it was screened from high-throughput screening (HTS) by 'automation-friendly' robotics, data processing, and control software in vitro -then it is easier to move to in vivo.…”

The flexibility of P-glycoprotein for its poly-specific drug binding from molecular dynamics simulations

“…For example, the multidrug efflux pump P-glycoprotein (P-gp) contributes to multidrug resistance (MDR) in about half of human cancers. P-gp encoded by a single gene in the human MDR1 gene is a member of the ATP binding cassette (ABC) family (Cascorbi et al, 2001;Chang et al, 2011a;Chen & Chen, 2010;Dean, Hamon, & Chimini, 2001;Sharom, 2008;Stefkova, Poledne, & Hubacek, 2004), which contributes to MDR in numerous types of human cancers and infectious diseases (Chang et al, 2011b(Chang et al, , 2011c(Chang et al, , 2011dChen, 2009Chen, , 2010Gottesman, Pastan, & Ambudkar, 1996;Wind & Holen, 2011). ABC importers and exporters are very important for their clinical relevance (Gottesman & Ling, 2006).…”

Chinese Medicine in the Management of New and Emerging Infectious Diseases

“…Chang et al [7] noted that "Traditional Chinese Medicine de novo derivatives may be suitable candidates of dual-targeting drugs for influenza". The authors also noted the use of standard modern Chinese medicine databases as a basic tool for new Chinese medicine-based drug discovery against new and emerging influenzas [8] .…”