The fibroblast growth factor receptor 1 (FGFR1) plays a crucial role in cancer development and progression, primarily through mechanisms involving carcinogenesis and angiogenesis. Aberrant FGFR1 signa Show more
The fibroblast growth factor receptor 1 (FGFR1) plays a crucial role in cancer development and progression, primarily through mechanisms involving carcinogenesis and angiogenesis. Aberrant FGFR1 signalling has been implicated in various cancers, including lung, breast, neck and urothelial carcinoma. Despite the recognized oncogenic potential of FGFR1, therapeutic strategies targeting its kinase domain remain inadequately explored. This underscores an urgent need for the development of novel FGFR1 inhibitors, particularly through de novo drug design approaches, to effectively counteract FGFR1-driven malignancies. This research aims to develop novel FGFR1 inhibitors through a multi-step approach involving fragment-based drug design, virtual screening, molecular dynamics simulation (MD) and density functional theory studies (DFT), with the goal of targeting FGFR1's kinase binding domain to inhibit tumor angiogenesis. Initially, known FGFR inhibitor molecules were retrieved and subjected to fragment-based drug designing and virtual screening. Through thorough analysis, molecules containing the pyrido[2,3-d]pyrimidine scaffold were identified as promising candidates. A pyrido[2,3-d]pyrimidine-based database containing 90,952 molecules was subsequently retrieved from PubChem and filtered using molecular docking-based virtual screening resulting 94 molecules having better binding affinity than derazantinib, reference drug. After pharmacokinetic profiling (ADME), and MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) studies, out of 94 molecules only 11 compounds with favorable pharmacokinetic properties and superior MM-GBSA binding free energies were selected. Docking-based screening revealed that selected 11 compounds demonstrated better binding scores than the reference drug, derazantinib. Among them, HIT1, was selected for 150ns molecular dynamics simulation to assess its conformational stability. DFT calculations further confirmed its bio-feasibility by analyzing the HOMO-LUMO energy gap. Overall, the selected lead compounds exhibited enhanced binding affinity, superior conformational stability, favorable pharmacokinetic and pharmacodynamic profiles compared to derazantinib. Present findings suggest that the identified hit molecules hold strong potential for inhibiting FGFR1's kinase domain and disrupting FGFR-associated tumor angiogenesis. Show less