Experimental and In-Silico investigations on novel bioactive 4-phenyl-2-thioxo-3,4-dihydro-1H-pyrido[1,2-a]pyrimido[4,5-d] pyrimidin-5(2H)-one

In this work, we report an efficient synthesis of pyrimidine fused novel 4-phenyl-2-thioxo-3,4-dihydro-1Hpyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5(2H)-one. The chemical structure of the title compound was ascertained by spectral techniques including UV-Visible, FT-IR, 1H NMR, 13C NMR and HRMS. The molecule was further subjected to quantum chemical calculations at the level of Density Functional Theory method employing B3LYP (Becke 3-parameter, Lee-Yang-Parr) level with 6-311++G(d,p) basis set. The computed characteristics of the molecule were investigated and interpreted comparing with the experimental values. Furthermore, Frontier Molecular Orbital (FMO) analysis was used to predict the energy properties and model the possible charge transfer within the molecule. The reactivity sites were identified by mapping the electron density into Molecular Electrostatic Potential (MEP). The stability of the molecule arising from hyper-conjugative interactions and charge delocalization were analyzed using Natural Bond Orbital (NBO) analysis. All the theoretical values were in good agreement with experimental studies. Docking studies was performed to examine binding sites of the title molecule and bioactivity scores indicated that the ligand's pharmacokinetic and pharmacological properties are sufficiently additive and shows the drug-likeness of the synthesized molecule. The study was validated by i) redocking the N3-peptide inhibitor and superimposing them onto co-crystallized complex and ii) protein ligand complex. Molecular dynamics simulations were performed for 50 ns to assess the conformational stability and fluctuations of protein-ligand complexes during the simulation.