Targeting Peptidyl-prolyl Cis-trans Isomerase NIMA-interacting 1 - A Structure-based Virtual Screening Approach to Find Novel Inhibitors

Aug 31, 2026

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is an enzyme that isomerizes phosphorylated serine or threonine motifs adjacent to proline residues, operating in multiple signaling pathways and influencing the development of diverse cancers. The study designs a computational pipeline to evaluate new triterpenoids against Pin1, combining molecular docking, pharmacophore filtering, structural clustering, molecular dynamics simulations, and binding free energy calculations. Triterpenoids from neem replicate Pin1 substrate-peptide binding and destabilize Pin1 with high affinity, with conclusions supported by experimental data.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages13

Reading Time33 min

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Introduction

Materials and Methods

Pin1 Structure Prediction

Compounds Library

# 1.INTRODUCTION Cancer is one of the leading causes of death worldwide,and it is expected that its incidence will increase in the follow-ing years [1].Currently,the development of target-baseddrugs has transformed cancer therapy in humans,and com-puter-aided drug design techniques have modified our ap-proaches for obtaining new candidates of drugs with time-saving and cheaper processes [2-8], Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1(Pinl)plays an important role in cancer development byisomerizing phosphorylated serine or threonine motifs adja-cent to proline residues (pSer/Thr-Pro motifs)[9-12]. ARTICLEHTSTORY Received:June 26,2019 Revised:Septznber 11,20J9 Aceypued.Octoher 10.20T9 DO₁:102174//5734699/5666797025714009 CrossMark Targeting Peptidyl-prolyl Cis-trans Isomerase NIMA-interacting 1: A Structure-based Virtual Screening Approach to Find Novel Inhibitors Kaue Santana da Costa1,\#,Joao M.Galúcio¹\#,Deivid Almeida de Jesus¹,Guelber Cardoso Gomes².Anderson Henrique Lima e Lima²,Paulo S.Taube¹,Alberto M.dos Santos'and Jerônimo Lameira³, Tnstirute of Biodiversib.Federal University of Western Para,Santarem,Para,Brazit²nstitute of PharmaceuticalSciences,Federal University of Para,66075-110.Belem,Para.Brazil:³Tnstitute of Biological Sciences.FederalUniversity of Para,66075-110.Belém,Pará,Brazil Abstract:Background:Peptidyl-prolyl cis-trans isomerase NIMA-interacting I(Pinl)is an enzyme that isomerizes phosphorylated serine or threonine motifs adjacent to proline residues.Pinlhas important roles in several cellular signaling pathways,consequently impacting the developmentof multiple iypes of cancers. Methods:Based on the previously reported inhibitory activity of pentacyclic triterpenoids isolatedfrom the gum resin of Boswellia genus against Pinl,we designed a computational experiment us-ing molecular docking,pharmacophore filtering,and structural clustering allied to molecular dy-namics(MD)simulations and binding free energy calculations to explore the inhibitory activity ofnew triterpenoids against Pinl structure. Results:Here,we report different computational evidence that triterpenoids from neem(Aza-dirachta indica A.Juss),such as 6-deacetylnimbinene,6-Oacetylnimbandiol,and nimbolide,repli-cate the binding mode of the Pinl substrate peptide,interacting with high affinity with the bindingsite and thus destabilizing the Pinl structure. Conclusions:Our results are supported by experimental dala,and provide interesting structural in-sights into their molecular mechanism of action,indicating that their structural scaffolds could beused as a start point to develop new inhibitors against Pin1, Keywords:Cancer targeting,peptidyl-prolyl isomerase.triterpenoids.molecular modeling,natural products.virtual screening. The dysregulation of Pinl expression has a high impact oncancer development,and its overexpression is related to can-cer prognosis and treatment [13-17].Pinl overexpressionleads to the activation of over 42 oncogenes and growth fac-tors and inactivation of more than 20 tumor suppressors andgrowth inhibitors [18-28].The inhibition of Pinl leads to thedepletion of various molecular targets cncoded by oncogenes[29-31]. Different studies have also reported Pinl inhibitors,suchas juglone [32],PiB [33],elemonic acid |34],epigallocate-chin-3-gallate [35],dexamethasone-21-phosphate [36],bu-parvaquone [37].D-PEPTIDE [38,39]and AIl-Trans Retin-oic Acid(ATRA)[40].ATRA and D-PEPTIDE are structural-ly different,but both compounds bind to the Pinl active sitemimicking the interactions of the pSer/Thr-Pro motif.thenatural substrate of the isomerase[11,41].Although some ofthe known inhibitors act in vitro in nanomolar concentra-tions,the compounds are inactive or weakly active in cellsdue to the presence of negatively-charged phosphate or car- boxylate groups that prevent the passage through the cellmembrane.In addition to the high side effects of these com-pounds,there exists a common

FAQs

What role does Pin1 play in cancer development?

Pin1 isomerizes pSer/Thr-Pro motifs adjacent to proline residues, affecting multiple cellular signaling pathways. Its dysregulation and overexpression drive oncogene activation and tumor suppressor inactivation, while inhibition depletes molecular targets encoded by oncogenes.

How were Pin1 structures prepared for the virtual screening workflow?

Crystallographic structures of Pin1 bound to D-PEPTIDE and ATRA were retrieved from the Protein Data Bank. The Pin1 wild-type sequence from UniProtKB was remodeled using homology modeling in Modeller, then the modeled structure was minimized in Amber by two optimization stages and protonation states were assessed via pKa calculations using PROPKA3 and the PDB2PQR server.

Which computational methods were used to discover potential Pin1 inhibitors?

The approach used pharmacophore filtering, molecular docking, and structural clustering, followed by molecular dynamics simulations and binding free energy calculations to assess inhibitory potential against Pin1.

Aug 31, 2026

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