Identification of (1E, 3E)-1, 3-bis [(2-hydroxy1-naphthyl) methylene] Urea as Mutated MAP Kinase P38 Inhibitor through Reverse Pharmacophore Mapping Approach: Green Synthesis, Characterisation and in silico Docking analysis

Introduction: Investigations on Schiff bases are one of the current pharmaceutical research trends due to their broad-spectrum biological activities and unique structural features such as intramolecular hydrogen bond formation, unsaturated C-N bond, the high mobility of hydrogen-bonded proton and pseudo aromatic ring formation. Aim: Current work is an attempt to discover the therapeutic potential of such structurally related Schiff bases compounds1-[(E)-[6-[(E)-(2-hydroxy-1-naphthyl) methyleneamino]- 2-pyridyl] iminomethyl] naphthalen-2-ol; P(a), (E)-1-(2-methoxy-1-naphthyl)-N-[6- [(E)- (2-methoxy-1- naphthyl) methyleneamino]-2-pyridyl] methanimine; P(b), (E)-1- (1-naphthyl)- N-[6-[(E)-1-naphthylmethyleneamino]-2-pyridyl] methanimine; P(c) and (1E,3E)-1,3-bis [(2-hydroxy-1-naphthyl)methylene]urea; P2(a). Materials and Methods: Reverse pharmacophore approach was used to identify the Mutated MAP Kinase P38 as the potent target for these selected compounds. The molecular docking studies were performed by using the glide module of Schrödinger Software suite and the Molecular Dynamics simulations were performed by using GROMACS 5.1 with OPLS force field. The in silico ADMET studies for all the compounds were performed using the online server SwissADME. The interesting results obtained from docking, dynamic simulation and ADMET properties of P(a), P(b), P(c) and P2(a) led to the synthesis and characterisation of these compounds. Results: The docking and simulation studies showed the Schiff base P2(a) has the highest binding affinity. The ADMET profile inclusive of oral-bioavailability and physicochemical properties shown by this P2(a) proves that it is the most pertinent lead molecule for a novel drug design. Conclusion: Hence, this work identifies the potential drug-like molecule (1E, 3E)-1,3-bis[(2-hydroxy-1-naphthyl) methylene] urea; P2(a) as Mutated MAP Kinase P38 inhibitor and provides the scope of advance in vivo studies to further explore the therapeutic potential of such compounds.