Identification of a natural antagonist for signal transducer and activator of transcription 3 (STAT3) by computational approach

The transcription factor family includes the cluster protein signal transducer and activator of transcription 3 (STAT3). Colorectal cancer (CRC) is predisposed to develop and spread when STAT 3 is abnormally activated because it speeds up cell division, prevents differentiation, and suppresses apoptosis. Only a small number of phytochemicals such as curcumin have been solidly demonstrated in clinical trials to lower the risk of CRC based on dose as well as confounding variables. Enthused by literature citations, we aimed in the present work to design novel antagonists against STAT3 using phytocompounds of two medicinal plants (Catharanthus roseus and Moringa oleifera) by integration of in-vivo and in-silico strategy. In-silico analysis was intended with receptor STAT3 (PDB ID: 6QHD), ligands (97 tentatively identified GC-MS compounds), and standard drugs (regorafenib and irinotecan) by docking and simulation analysis via tools such as Maestro v.11.9, LigPrep, Epik v.4.7, QikProp v.5.1, Glide v.8.2 of Schrodinger LLC-2019.1, and Desmond v.3.8. Docking studies exemplifies that STAT3 depicted better binding affinity with pyrrole (3,4-C) pyrrole-1-carboxylic acid, octadecanoic acid, and 2,3-dihydroxypropyl ester, (−7.266 kcal/mol, and −7.124 kcal/mol) as compared with standard drugs (regorafenib, and irinotecan). Further, the molecular dynamics analysis of these two lead complexes for 100 ns validates the stability, superiority of the vital interactions and also retained all over the trajectories besides fulfilling the ADMET criteria. Thus, the proposed leads act as valuable starting points and ideal candidates to be developed as drug candidates for CRC patients if synthesized and tested in-vitro, in-vivo, and in animal models after further detailed investigations.