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<p>Olanzapine (OLZ), a widely prescribed atypical antipsychotic for psychiatric disorders, is associated with cardiometabolic disorders (CMDs). <i>Lagenaria siceraria</i> has demonstrated cardioprotective properties and potential benefits in CMD(s). This study investigates the mechanisms of <i>L. siceraria</i> in OLZ-induced CMD(s) using computational approaches. Bioactives from <i>L. siceraria</i> were retrieved from PubChem and their targets predicted via SuperPred DB (<i>p</i> ≥ 0.7). CMD-related protein targets of OLZ were identified using GeneCards and enriched using STRING analysis. Cytoscape (v3.6.1) was employed to construct a bioactives-target-pathway network. Molecular docking was conducted using AutoDock Vina via the POAP pipeline, followed by 100 ns molecular dynamics simulations in GROMACS to evaluate stability and interactions. Nineteen bioactives were identified, with eleven modulating 24 protein targets, while OLZ regulated 54 CMD(s)-related targets. Gene enrichment analysis revealed <i>IGF-1R</i>,<i> TNF-α</i>, isoquercitrin, and cucurbitacin H as key modulators of the MAPK, calcium, cAMP, AMPK, and apoptosis pathways. Docking studies showed <i>IGF-1R</i>-isoquercitrin (-7.7&#xa0;kcal/mol) and <i>TNF-α</i>-cucurbitacin H (-9.9&#xa0;kcal/mol) as having the most favourable binding energies, supported by stable molecular dynamics and significant intermolecular interactions during simulations. Targeting these critical genes and pathways may improve drug discovery efforts and provide novel strategies for CMD(s) management in psychiatric patients. Experimental validation is necessary to confirm the cardioprotective effects of <i>L. siceraria</i> in OLZ-induced CMD(s), potentially offering therapeutic insights for mitigating cardiometabolic risks in antipsychotic treatments.</p>

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Pharmacoinformatic insights: cardioactive bioflavonoids and triterpenoids from Lagenaria siceraria in mitigating Olanzapine-induced cardiotoxicity

  • 期刊论文

  • 发表日期：

    2025年12月19日

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  • Faizan A. Beerwala,
  • Shruti V. Kolambkar,
  • Adilmehadi Karikazi,
  • Rajshree Virge,
  • Akanksha Desai,
  • Sunny Gupta,
  • Harish R. Darasaguppe,
  • Nayeem A. Khatib,
  • Subarna Roy

摘要

Olanzapine (OLZ), a widely prescribed atypical antipsychotic for psychiatric disorders, is associated with cardiometabolic disorders (CMDs). Lagenaria siceraria has demonstrated cardioprotective properties and potential benefits in CMD(s). This study investigates the mechanisms of L. siceraria in OLZ-induced CMD(s) using computational approaches. Bioactives from L. siceraria were retrieved from PubChem and their targets predicted via SuperPred DB (p ≥ 0.7). CMD-related protein targets of OLZ were identified using GeneCards and enriched using STRING analysis. Cytoscape (v3.6.1) was employed to construct a bioactives-target-pathway network. Molecular docking was conducted using AutoDock Vina via the POAP pipeline, followed by 100 ns molecular dynamics simulations in GROMACS to evaluate stability and interactions. Nineteen bioactives were identified, with eleven modulating 24 protein targets, while OLZ regulated 54 CMD(s)-related targets. Gene enrichment analysis revealed IGF-1R, TNF-α, isoquercitrin, and cucurbitacin H as key modulators of the MAPK, calcium, cAMP, AMPK, and apoptosis pathways. Docking studies showed IGF-1R-isoquercitrin (-7.7 kcal/mol) and TNF-α-cucurbitacin H (-9.9 kcal/mol) as having the most favourable binding energies, supported by stable molecular dynamics and significant intermolecular interactions during simulations. Targeting these critical genes and pathways may improve drug discovery efforts and provide novel strategies for CMD(s) management in psychiatric patients. Experimental validation is necessary to confirm the cardioprotective effects of L. siceraria in OLZ-induced CMD(s), potentially offering therapeutic insights for mitigating cardiometabolic risks in antipsychotic treatments.