Rational design of PIN1 inhibitors for cancer treatment based on conformational diversity analysis and docking based virtual screening

Abstract

The parvulin PIN1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1), is the only enzyme capable of isomerizing prolines of phospho-Serine/Threonine-Proline motifs. PIN1 binds to a subset of proteins and plays an essential role in regulating protein function post-phosphorylation control. Furthermore, the activity of PIN1 regulates the outcome of the signalling of proline-directed kinases (e.g. MAPK, CDK, or GSK3) and thus regulates cell proliferation and cell survival. For these reasons, PIN1 inhibitors are interesting since they may have therapeutic implications for cancer. Several authors have already reported that the non-structural point mutation Trp34Ala prevents PIN1 from interacting with its downstream effector proteins. In this work, we characterized PIN1 structurally, intending to explore new inhibition targets for the rational design of pharmacological activity compounds. Through a conformational diversity analysis of PIN1, we identified and characterized a highly specific druggable pocket around the residue Trp34. This pocket was used in a high-throughput docking screening of 450,000 drug-like compounds, and the top 10 were selected for re-docking studies on the previously used conformers. Finally, we evaluated the binding of each compound by thermal shift assay and found four molecules with a high affinity for PIN1 and potential inhibitory activity. Through this strategy, we achieved novel drug candidates with the ability to interfere with the phosphorylation-dependent actions of PIN1 and with potential applications in the treatment of cancer.

Communicated by Ramaswamy H. Sarma

Keywords:

• Drug design
• PIN1 inhibitors
• conformational diversity
• cancer

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The present study was supported by grants from Quilmes National University (UNQ), National Research Council (CONICET), the National Agency for the Promotion of Science and Technology (ANPCyT) and Cancer National Institute (INC-Argentina). Pablo Lorenzano Menna, Daniel Eduardo Gomez and Diego Mengual Gómez are members of CONICET. Romina Armando and Marina Pifano are postdoctoral fellows from CONICET. Julian Maggio is a doctoral fellow from CONICET. Patricio Chinestrad is grade student fellow from UNQ. The authors wish to express their gratitude to Tadeo Saldaño, Mauricio Sica and Maria Laura Terrone for critical reading of the manuscript.