Comparative theoretical analysis using DFT & MP2 calculations, ADMET profiling and docking studies of the drug telotristat ethyl

The title drug, Ethyl(2S)-2-amino-3-(4{2-amino-6-[(1R)-1-[4-chloro-2-(3-methyl-1H-pyrazol-1-yl) phenyl]-2,2,2-trifluoroethoxy] pyrimidin-4-yl}phenyl)propanoate was reported for carcinoid syndrome diarrhea and approved by FDA in the year 2017. DFT (B3LYP) and Moller-Plesset Second Order (MP2) quantum chemical calculations in the 631G basis set were used to optimize the drug and evaluate the global and local reactivity descriptors. Molecular docking was performed against the tryptophan hydroxylase-1 inhibitor protein to study the binding interactions of the drug with the protein and rationalize the structure-activity relationship. The bond length between drug and protein established the presence of good binding with more interaction or reactivity. Fukui functions were invoked to describe the reactivity and stability of the drug molecule. ADMET profiling of the drug molecule predicts poor solubility and limited absorption in the gastrointestinal tract. BOILED Egg representation displayed low absorption, impermeability to the Blood-Brain barrier, and induced P-gp Substrate. Descriptor parameters were compared between DFT and MP2 optimized structures for each atom, and the most reactive and stable atoms were reported. The current research focuses on the structural and bioactive properties of the title molecule. The study was conducted further to find suitable reactivity centers. This aspect would help to evaluate more reactivity patterns of such types of molecules in future. [Display omitted] •Telotristat ethyl, a drug for Carcinoid Syndrome Diarrhea, was optimized by DFT and MP2 calculations in 631G basis set.•Global and local reactivity descriptors were evaluated from the HOMO-LUMO energy values.•Fukui Function using DFT predicted the most electrophilic and nucleophilic sites within the molecule.•Docking studies showed good binding interactions with the protein Tryptophan Hydroxylase-1 inhibitor.•ADME profiling and the theoretical studies identified the most reactive atoms of the drug.