Virtual screening and molecular dynamics investigations using natural compounds against autotaxin for the treatment of chronic pain.

ABSTRACT

Chronic pain is a common and debilitating condition with a huge social and economic burden worldwide. Currently, available drugs in clinics are not adequately effective and possess a variety of severe side effects leading to treatment withdrawal and poor quality of life. Recent findings highlight the potential role of autotaxin (ATX) as a promising novel target for chronic pain management, extending beyond its previously established involvement in arthritis and other neurological disorders, such as Alzheimer's disease. In the present study, we used a virtual screening strategy by targeting ATX against commercially available natural compounds (enamine- phenotypic screening library) to identify the potential inhibitors for the treatment of chronic pain. After initial identification using molecular docking based virtual screening, molecular mechanics (MM/GBSA), ADMET profiling and molecular dynamics simulation were performed to verify top hits. The computational screening resulted in the identification of fifteen top scoring structurally diverse hits that have free energy of binding (ΔG) values in the range of -25.792 (for compound Enamine_1850) to -74.722 Kcal/mol (for compound Enamine_1687). Moreover, the top-scoring hits have favourable ADME properties as calculated using in-silico algorithms. Additionally, the molecular dynamics simulation revealed the stable nature of protein-ligand interaction and provided information about amino acid residues involved in binding. This study led to the identification of potential autotaxin inhibitors with favourable pharmacokinetic properties. Identified hits may further be investigated for their safety and efficacy potential using in-vitro and in-vivo models of chronic pain.Communicated by Ramaswamy H. Sarma.