Molecular Modeling, Synthesis and Pharmacological Screening of Rock-2(RHO Kinase-2) Inhibitors for Multiple Sclerosis

Abstract

Multiple Sclerosis is an “immune mediated disease”, etiology of MS is still an area of discovery, but factors like immunology, environmental and genetical defects might play role. 2.3 million People in the world are suffering through MS, although the number may be much higher as many people with MS remain undiagnosed. People are generally diagnosed between the ages of 25 and 35, from total patients 3-5% is children and can occur in much older adults. Rho kinase belongs to serine-threonine family and has 160 kDa of molecular weight. With two isoforms namely ROCK-1 and ROCK-2, it has vital role to play in physiological function of cell contraction, proliferation and migration. Its inhibition has been proven useful in various medical conditions like multiple sclerosis, inflammatory disorders, myocardial ischemia, hypertension, erectile dysfunction, glaucoma, cancer migration and spinal cord injury. In here, various computational methods were used for the designing of molecules. Ligand based approaches like 3D-QSAR and pharmacophore modelling were utilized with other techniques like virtual screening, molecular docking, in silico ADMET studies. 38 ROCK-2 inhibitors were selected after extensive literature survey for performing 3D-QSAR studies, distill based alignment was used. On the basis of contour maps favourable and unfavourable region were identified.8 different structures were taken for the pharmacophore generation. Pharmacophore model was developed using GALAHAD module of Sybyl X. The best model was selected which showed 2 hydrophobic, 1 donor atom, 2 acceptor site as essential features. It was further validated through GH and ROC method. Virtual screening which was performed on the generated model which retrieved 40 compounds showed Qfit value greater than 80%. Molecular docking studies were carried out on designed molecules using 2F2U as ROCK- 2 protein. Best scoring compounds were further synthesized and were further characterized using IR, 1H NMR, 13C NMR and Mass spectrometry.