AI-designed macitentan derivatives show superior VEGFR1 and ET-1 receptor binding affinity for preeclampsia

Preeclampsia is a severe hypertensive disorder of pregnancy characterized by angiogenic imbalance and endothelial dysfunction. This pathology is primarily driven by the overexpression of soluble fms-like tyrosine kinase-1 (sFlt-1) and upregulation of endothelin-1 (ET-1). Current standard-of-care often involves symptom management or early delivery, highlighting a critical need for targeted therapies. Dual targeting of both VEGFR1 (implicated in sFlt-1 signaling) and the ET-1 receptor offers a promising strategy to address these core mechanisms, leveraging existing knowledge of endothelin receptor antagonists like macitentan.

Researchers utilized macitentan, a known dual ETA/ETB antagonist, as a scaffold for AI-assisted molecular diversification. A comprehensive computational pipeline was employed to generate and optimize derivatives. This involved molecular docking to predict binding modes, pharmacophore modeling to identify key structural features, and molecular dynamics (MD) simulation over 500 ns to assess complex stability. Further analysis included DFT (Density Functional Theory) for electronic properties, MM/GBSA for binding energy calculations, and ADMET profiling to predict drug-likeness, absorption, distribution, metabolism, excretion, and toxicity. The goal was to identify compounds with improved dual inhibition of VEGFR1 and ET-1 receptor compared to the parent compound.

The computational analysis identified two key derivatives with enhanced binding profiles. Derivative 24 demonstrated high binding affinity toward VEGFR1 (-7.7 kcal/mol), while Derivative 15 exhibited superior interaction with the ET-1 receptor (-9.2 kcal/mol). Both derivatives computationally outperformed macitentan in their respective primary targets. MD simulations confirmed the stability of these complexes, with RMSD stabilization observed around 0.2-0.3 nm and consistent hydrogen bonding throughout the 500 ns simulation. MM/GBSA binding energies further supported these strong interactions, showing -17.15 kcal/mol for Derivative 24-VEGFR1 and -28.72 kcal/mol for Derivative 15-ET-1 receptor. DFT results indicated reduced HOMO-LUMO gaps (3.55 eV for Derivative 24; 3.30 eV for Derivative 15), suggesting favorable reactivity, while MEP analysis confirmed optimal electrostatic potential for target engagement. Pharmacophore and ADMET profiling predicted improved drug-likeness, high gastrointestinal absorption, and reduced toxicity for these novel compounds.

Derivative 15 showed superior interaction with ET-1 receptor (-9.2 kcal/mol), while Derivative 24 exhibited high binding affinity toward VEGFR1 (-7.7 kcal/mol), both outperforming macitentan.