Fragment-based investigation of thiourea derivatives as VEGFR-2 inhibitors: a cross-validated approach of ligand-based and structure-based molecular modeling studies.
J Biomol Struct Dyn
; 42(2): 1047-1063, 2024.
Article
em En
| MEDLINE
| ID: mdl-37029768
ABSTRACT
Angiogenesis is mediated by the vascular endothelial growth factor (VEGF) that plays a key role in the modulation of progression, invasion and metastasis, related to solid tumors and hematological malignancies. Several small-molecule VEGFR-2 inhibitors are marketed, but their usage is restricted to specific cancers due to severe toxicities. Therefore, cost-effective novel small molecule VEGFR-2 inhibitors may be an alternative to overcome these adverse effects. Here, a set of thiourea-based VEGFR-2 inhibitors were considered for a combined fragment-based QSAR technique, structure-based molecular docking followed by molecular dynamics simulation studies to acquire insights into the key structural attributes and the binding pattern of enzyme-ligand interactions. Noticeably, amine-substituted quinazoline phenyl ring and a higher number of nitrogen atoms, and the hydrazide function in the molecular structure are crucial for VEGFR-2 inhibition whereas methoxy groups are detrimental to VEGFR-2 inhibition. The MD simulation study of sorafenib and thiourea derivatives explored the significance of urea and thiourea moiety binding at VEGFR-2 active site that can be utilized further in the future to design molecules for greater binding stability and better VEGFR-2 selectivity. Therefore, such findings can be beneficial for the development of newer VEGFR-2 inhibitors for further refinement to acquire better therapeutic efficacy.Communicated by Ramaswamy H. Sarma.
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MEDLINE
Assunto principal:
Neoplasias
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Antineoplásicos
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article