IN-SILICO BINDING AFFINITIES OF ALKALOID COMPOUNDS ON NICOTINIC ACETYLCHOLINE RECEPTOR α3β4 FOR SMOKING CESSATION TREATMENT

Nicotinic acetylcholine receptor α3β4 is considered as a potential target for anti-smoking drug discovery. In this study, in-silico approaches, including molecular docking and molecular dynamics simulation were applied to investigate binding affinities of 300 alkaloids into the α3β4 (Pdb id: 6PV8). The docking results showed that most of the alkaloids fitted well into the binding pocket of α3β4. The top hit compounds were A122 (indole alkaloid) and A128 (tropane alkaloid) with their binding affinities of less than -8.0 kcal.mol^-1 and the interactions with key residue, Trp149. Structures and binding affinities relationships between the indole and tropane compounds with the α3β4 emphasized the important roles of indole backbone and the benzyl substituent at C3 of tropane scaffold in forming the hydrophobic interactions making good binding affinities. Molecular dynamics simulations revealed the potential of A128 to binding stably with the α3β4 during 20 ns. Binding free energy of the complex A128 – α3β4 was calculated based on Molecular Mechanics – Poisson Boltzmann Surface Area (MM-PBSA) method, which also emphasized the importance of electrostatic contacts over van der Waals interactions for proper binding. Hence, A128 can be additionally explored by in-vitro and in-vivo experiments for further confirmation of its smoking cessation treatment.