LAUSR

Virus mutates quickly and develops drug resistance over time if targeted directly. A possible alternative for drug design is to target cellular proteins that the virus needs. To be viable, the drug ought to inhibit the cellular protein only when bound by viral protein. We use a particular virus–host complex to illustrate how to identify such an inhibitor. HIV-1 uses its viral protein Tat to hijack a cellular protein complex Cdk9/Cyclin T1, termed positive elongation factor b (p-TEFb), to enhance its viral transcription. Tat binds to both Cdk9 and Cyclin T1 and thus creates a second pathway between Cdk9 and Cyclin T1 that is distinct from the Cdk9/Cyclin T1 interface. Dynamical network analysis based on molecular dynamics simulations reveals a pocket on Cdk9 that becomes allosterically correlated with the interface via the second pathway. Computational docking simulations indicate a noticeable weakening of the interface formation of Cdk9 and Cyclin T1 upon binding of a small molecule F07#13 to the pocket and Tat to the complex. We verified experimentally via site mutagenesis that F07#13 indeed targets this pocket and diminishes the kinase activity of Cdk9 in the presence of Tat. Together with previous experiments that showed little effect of F07#13 in the absence of Tat, the proposed computational framework therefore provides some insights on how to design antiviral drugs with reduced risk of drug resistance.