TULP3 NLS inhibition: an in silico study to hamper cargo transport to nucleus

Abstract

TULP3 is involved in cell regulation pathways including transcription and signal transduction. In some pathological states like in cancers, increased level of TULP3 has been observed so it can serve as a potential target to hamper the activation of those pathways. We propose a novel idea of inhibiting nuclear localization signal (NLS) to interrupt nuclear translocation of TULP3 so that the downstream activations of pathways are blocked. In current in silico study, 3D structure of TULP3 was modeled using 8 different tools including I-TASSER, CABS-FOLD, Phyre2, PSIPRED, RaptorX, Robetta, Rosetta and Prime by Schrödinger. Best structure was selected after quality evaluation by SAVES and implied for the investigation of NLS sequence. Mapped NLS sequence was further used to dock with natural ligand importin-α as control docking to validate the NLS sequence as binding site. After docking and molecular dynamics (MD) simulation validation, these residues were used as binding side for subsequent docking studies. 70 alkaloids were selected after intensive literature survey and were virtually docked with NLS sequence where natural ligand importin-α is supposed to be bound. This study demonstrates the virtual inhibition of NLS sequence so that it paves a way for future in-vivo studies to use NLS as a new drug target for cancer therapeutics.

Communicated by Ramaswamy H. Sarma

Keywords:

• Tubby protein
• nuclear localization signal
• alkaloids
• autodock vina
• inhibition constant
• protein modeling
• MD simulation

Disclosure statement

The authors declare no conflict of interest.

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Author contributions

AT and MN designed the project; AT and RMM performed the experiments, evaluated and interpreted the data; AT, RMM, MA, MH and IT prepared the draft manuscript; MS, MSA and MN finalized the manuscript. All authors approved the final version of the manuscript.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.