{"title":"Identification of potential inhibitors for MAP4K4 in glaucoma using Meta-Dynamics-Based dissociation free energy calculation.","authors":"Vanshika Rustagi, Rashmi Rameshwari, Indrakant Kumar Singh","doi":"10.1016/j.brainres.2024.149300","DOIUrl":null,"url":null,"abstract":"<p><p>Glaucoma, a prevalent eye ailment causing irreversible vision loss, affects over 295 million individuals globally, necessitating the exploration of novel therapeutic avenues. Despite extensive research on targets like the phosphodiesterase enzyme and rho kinase, the potential of MAP4K4 in glaucoma remains untapped. This study aims to identify potent MAP4K4 inhibitors to counteract retinal cell apoptosis and oxidative stress associated with glaucoma. Using HTVS and XP docking, 911,059 compounds were screened. The MMGBSA calculation and pharmacokinetics analysis were used to shortlist the compounds. After performing 75 molecular dynamics simulations, further meta-dynamics were employed to calculate dissociation-free energy and find potential MAP4K4 inhibitors. Findings indicated that ZINC06717217 and ZINC38836256 exhibited remarkable promise, with docking scores of -9.57 and -11.12 and MMGBSA binding energies of -91.07 kcal/mol and -87.52 kcal/mol, respectively. Comparative analysis with the reference compound Q27453723 underscored their superior stability, requiring dissociation-free energies of -15.11 kcal/mol and -12.46 kcal/mol to disengage from the docked complex. This underscored their robust binding affinity. ZINC06717217 and ZINC38836256 show promising stability and strong binding to the MAP4K4 protein. Hence, these findings are promising in inhibiting MAP4K4 for glaucoma treatment, potentially leading to more effective treatment and curing blindness. KEY MESSAGES: First to incorporate the dissociation-free energy for identifying compounds for glaucoma treatment. In-silico analysis showed that ZINC06717217 and ZINC38836256 are promising compounds for targeting MAP4K4.</p>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":null,"pages":null},"PeriodicalIF":2.7000,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.brainres.2024.149300","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Glaucoma, a prevalent eye ailment causing irreversible vision loss, affects over 295 million individuals globally, necessitating the exploration of novel therapeutic avenues. Despite extensive research on targets like the phosphodiesterase enzyme and rho kinase, the potential of MAP4K4 in glaucoma remains untapped. This study aims to identify potent MAP4K4 inhibitors to counteract retinal cell apoptosis and oxidative stress associated with glaucoma. Using HTVS and XP docking, 911,059 compounds were screened. The MMGBSA calculation and pharmacokinetics analysis were used to shortlist the compounds. After performing 75 molecular dynamics simulations, further meta-dynamics were employed to calculate dissociation-free energy and find potential MAP4K4 inhibitors. Findings indicated that ZINC06717217 and ZINC38836256 exhibited remarkable promise, with docking scores of -9.57 and -11.12 and MMGBSA binding energies of -91.07 kcal/mol and -87.52 kcal/mol, respectively. Comparative analysis with the reference compound Q27453723 underscored their superior stability, requiring dissociation-free energies of -15.11 kcal/mol and -12.46 kcal/mol to disengage from the docked complex. This underscored their robust binding affinity. ZINC06717217 and ZINC38836256 show promising stability and strong binding to the MAP4K4 protein. Hence, these findings are promising in inhibiting MAP4K4 for glaucoma treatment, potentially leading to more effective treatment and curing blindness. KEY MESSAGES: First to incorporate the dissociation-free energy for identifying compounds for glaucoma treatment. In-silico analysis showed that ZINC06717217 and ZINC38836256 are promising compounds for targeting MAP4K4.
期刊介绍:
An international multidisciplinary journal devoted to fundamental research in the brain sciences.
Brain Research publishes papers reporting interdisciplinary investigations of nervous system structure and function that are of general interest to the international community of neuroscientists. As is evident from the journals name, its scope is broad, ranging from cellular and molecular studies through systems neuroscience, cognition and disease. Invited reviews are also published; suggestions for and inquiries about potential reviews are welcomed.
With the appearance of the final issue of the 2011 subscription, Vol. 67/1-2 (24 June 2011), Brain Research Reviews has ceased publication as a distinct journal separate from Brain Research. Review articles accepted for Brain Research are now published in that journal.