Graphical Abstract
Fragment based novel drug identification and its validation through use of
molecular dynamics and simulations.
Abstract
Comparing primary microcephaly genes with glioblastoma expression profiles
reveals potential oncogenes, with proteins that support growth and survival in
neural stem/progenitor cells likely retaining critical roles in glioblastoma.
Identifying such proteins in familial and congenital microcephalic disorders
offers promising targets for brain tumor therapy. Among these, KIF11, a kinesin
motor protein (KSP), stands out as a significant oncogene. Expression analyses
across various cancer types, including glioblastoma, demonstrate its
overexpression in brain tumor patients. Using a targeted fragment-based drug
discovery approach, we explored alternative small molecule inhibitors for KIF11.
Existing drugs, such as ispinesib, are limited by side effects and multidrug
resistance. Through molecular docking and simulations, we identified three
candidate drug fragments. Further analysis confirmed that Mol-121026 exhibits a
more stable interaction with KIF11 compared to ispinesib. Detailed analyses
indicate that Mol-121026 binds to the same active site as the reference drug,
effectively inhibiting KIF11ʼs mechano-chemical activity. Importantly,
Mol-121026, a derivative of 3-phenyl-1H-pyrazol-5-carboxylic acid, offers a
promising alternative due to its lower molecular complexity, ability to target
allosteric sites, and potential for optimization into a potent and effective
drug candidate. Our findings identified Mol-121026 as a top candidate with a
docking score of −10.2 kcal/mol and MM/GBSA binding energy of −19.10 kcal/mol.
Molecular dynamics simulations revealed stable interactions with key residues
GLU116 and GLU118, supporting its potential as a promising KIF11 inhibitor.
Keywords
drug research - drug
regulation - anticancer drugs - cancer - central nervous
system disorders
