Inhibition of unfolded protein response (UPR) during cellular stress has been shown to render cells to be more sensitive against various stress-inducing treatment methods such as chemotherapy. RtcA RNA cyclase is one of the main proteins involved in the UPR which is capable of converting cleaved 2'-phosphates end XBP1 mRNA to 2',3'-cyclic phosphate form. Inhibiting the action of RtcA might hence be a viable route towards cancer therapy.<br/>To achieve this goal, small molecule libraries were docked against the quality-verified RtcA homology model at both ATP binding pocket and RNA binding site (Figure 1). The stabilities of the best hits were confirmed by means of Molecular Dynamics and Metadynamics simulations. To enhance the selectivity, the best ATP and RNA binders were merged into a single molecule which might have the propensity to cover both ATP and RNA biding sites. The stability of the merged molecule was examined using <i>in silico </i>techniques, and provides a first attempt in designing novel RtcA inhibitors for therapeutic intervention.

Exploration of structure and inhibitors to RNA cyclase RtcA

ACS Spring Meeting 2021

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