Fragment-based investigation of thiourea derivatives as VEGFR-2 inhibitors: a cross-validated approach of ligand-based and structure-based molecular modeling studies

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

Keywords:

• VEGFR-2
• cancer
• thiourea
• fragment-based drug discovery
• QSAR
• molecular dynamics simulation

Acknowledgment

The authors are thankful to the Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India, and the Department of Pharmacy, BITS-Pilani Hyderabad Campus, Shamirpet, Hyderabad, India for proving the Research Facilities.

Disclosure Statement

The authors have no conflict of interest.

Additional information

Funding

SB is thankful to the Swami Vivekananda Merit-cum-Means (SVMCM) scholarship, Govt. of West Bengal, India for awarding the fellowship. BG is thankful to the Department of Health Research, India (File No. 11013_33_2021-GIA HR), Govt. of India and Council of Scientific and Industrial Research (CSIR-37(1722)/19/EMR-II), and DBT-BUILDER (BT/INF/22/SP42551/2021), Govt. of India for providing research grants. NA is thankful to the authority of Jadavpur University for providing a research grant to conduct the research work.