Rationale design and synthesis of new apoptotic thiadiazole derivatives targeting VEGFR-2: computational and <i>in vitro</i> studies
Walid E. Elgammal, Hazem Elkady, Hazem A. Mahdy, Dalal Z. Husein, Aisha A. Alsfouk, Bshra A. Alsfouk, Ibrahim M. Ibrahim, Eslam B. Elkaeed, Ahmed M. Metwaly, Ibrahim H. Eissa
Abstract
G0-G1 phase arrest. Interestingly, compound 14 also demonstrated a noteworthy pro-apoptotic effect in MCF-7 cells, with notable increases in early apoptosis (16.53%) and late apoptosis (29.57%), along with a slight increase in the population of necrotic cells (5.95%). Furthermore, compound 14 showed a significant drop in MCF-7 cells' ability to migrate and heal wounds. Additionally, compound 14 promoted apoptosis by boosting BAX (6-fold) while lowering Bcl-2 (6.2-fold). The binding affinities of the synthesized candidates to their target (VEGFR-2) were confirmed by computational investigations, including molecular docking, principal component analysis of trajectories (PCAT), and molecular dynamics (MD) simulations. Additionally, compound 14's stability and reactivity were investigated using density functional theory (DFT). These thorough results highlight compound 14's potential as a lead contender for additional research in the creation of anticancer drugs that target VEGFR-2. This work establishes a foundation for promising thiadiazole derivatives for future therapeutic developments in anticancer- and angiogenesis-related scientific fields.