Invokana (Canagliflozin) as a Dual Inhibitor of Acetylcholinesterase and Sodium Glucose Co-Transporter 2: Advancement in Alzheimer’s Disease- Diabetes Type 2 Linkage via an Enzoinformatics Study
Syed M.D. Rizvi, Shahnawaz Shakil, Deboshree Biswas, Shazi Shakil, Sibhghatulla Shaikh, Paramdeep Bagga and Mohammad A. Kamal
Affiliation: Department of Bio-Engineering, Integral University, Lucknow, UP-226026, India.
Keywords: Acetylcholinesterase, sodium glucose co-transporter, invokana, canagliflozin, docking.
Acetylcholinesterase (AChE) is a primary target for Alzheimer’s therapy while recently sodium glucose cotransporter
2 (SGLT2) has gained importance as a potential target for Type 2 Diabetes Mellitus (T2DM) therapy. The
present study emphasizes the molecular interactions between a new Food and Drug Administration (FDA) approved antidiabetic
drug ‘Invokana’ (chemically known as Canagliflozin) with AChE and SGLT2 to establish a link between the
treatment of T2DM and Alzheimer’s Disease (AD). Docking study was performed using ‘Autodock4.2’. Both
hydrophobic and π-π interactions play an important role in the correct positioning of Canagliflozin within SGLT2 and
catalytic site (CAS) of AChE to permit docking. Free energy of binding (ΔG) for ‘Canagliflozin-SGLT2’ interaction and
‘Canagliflozin - CAS domain of AChE’ interaction were found to be -10.03 kcal/mol and -9.40 kcal/mol, respectively.
During ‘Canagliflozin-SGLT2’ interaction, Canagliflozin was found to interact with the most important amino acid
residue Q457 of SGLT2. This residue is known for its interaction with glucose during reabsorption in kidney. However,
‘Canagliflozin-CAS domain of AChE’ interaction revealed that out of the three amino acids constituting the catalytic triad
(S203, H447 and E334), two amino acid residues (S203 and H447) interact with Canagliflozin. Hence, Invokana
(Canagliflozin) might act as a potent dual inhibitor of AChE and SGLT2. However, scope still remains in the
determination of the three-dimensional structure of SGLT2-Canagliflozin and AChE-Canagliflozin complexes by X-ray
crystallography to validate the described data. Since the development of diabetes is associated with AD, the design of new
AChE inhibitors based on antidiabetic drug scaffolds would be particularly beneficial. Moreover, the present
computational study reveals that Invokana (Canagliflozin) is expected to form the basis of a future dual therapy against
diabetes associated neurological disorders.
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