In silico screening of Annona muricata L. leaf constituents and derivatives towards selected Type 2 Diabetes Mellitus - related protein targets

Abstract

Background: Type 2 diabetes mellitus, or T2DM, is one of the world's most chronic health problems that is linked to numerous deaths and high health care expenses. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), protein-tyrosine phosphatase 1B (PTP1B) and mono-ADP-ribosyl transferase sirtuin-6 (SIRT6) were among the novel proteins and focus targets of diabetes research. Annona muricata is a commonly used natural remedy for several illnesses, including type 2 diabetes mellitus. However, most of these traditional claims have received few molecular evaluations.

Objectives: This study investigated the phytoconstituents and derivatives of the leaves of A. muricata by evaluating their binding affinities towards selected novel T2DM-related protein targets through in silicomethods.

Methodology: This study screened the potential lead compounds from the leaves of A. muricata by evaluating the binding energies (kcal/mol) of the parent compounds and derivatives with the targets compared to the native ligands and known substrates through molecular docking.

Results: The 8 parent compounds – the alkaloids coreximine and isolaureline, and phenolic compounds
chlorogenic acid, epicatechin, kaempferol, kaempferol 3-O-rutinoside, quercetin, and rutin were selected for bioisosteric modifications. Furthermore, after docking simulations of derivatives, compounds ACM018, ACM021, ACM024, ACM036, and ACM044, are the top 5 derivatives for 11β-HSD1. In PTP1B, ACM014, ACM020, ACM021, ACM024, and ACM028 are the top 5 ligands. Lastly, BCM008, BCM022, DCM004, DCM025, and DCM027 are the top 5 derivatives for SIRT6.

Conclusion: Based on the binding energies of the parent compounds and derivatives, they exhibited comparable binding affinity as the controls. Moreover, the designed derivatives may be synthesized and further investigated for potential biological effects towards 11β-HSD1, PTP1B, and SIRT6 through in vitro and in vivo experiments.