Prospecting and Structural Insight into the Binding of Novel Plant-Derived Molecules of Leea indica as Inhibitors of BACE1

Abstract

Alzheimer disease (AD) can be considered the most common age-related neurodegenerative disorder, and also, an important cause of death in elderly patients. A number of studies found the correlation of this disease pathology with BACE1 inhibitor and it is also evident that BACE1 inhibitor can function as a very potent treatment strategy in treating AD. In the present study, we aimed to prospect for novel plant-derived BACE1 inhibitors from Leea indica and to realize the structural basis of their interactions and mechanisms using combined molecular docking and molecular dynamics based approaches. An extensive library of Leea indica plant-derived molecule was compiled and computationally screened for inhibitory action against BACE1 by using virtual screening approaches. Furthermore, induced fit docking and classical molecular dynamics along with steered molecular dynamics simulations were employed to get insight the binding mechanisms. Two triterpenoids, ursolic acid and lupeol were identified through virtual screening; wherein, lupeol showed better binding free energy in MM/GBSA, MM/PBSA and MM/GBVI approaches. Furthermore classical and steered dynamics revealed the favourable hydrophobic interactions between the lupeol and the residues of flap or catalytic dyad of BACE1; however, ursolic acid showed disfavorable interactions with the BACE1. This study, therefore, unveiled the lupeol as a potent BACE1 inhibitor from a manually curated dataset of Leea indica molecules, which may provide a new dimension of designing novel BACE1 inhibitors for AD therapy.

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

“…Moreover, other studies indicated that lupeol have neuroprotective property . It has also been reported that lupeol inhibits BACE1 with an IC 50 value of 5.12 μM …”

“…Furthermore, although both compounds formed hydrophobic interactions with Tyr71 residue at the flap region, however, none of them was able to interact with the catalytic aspartic acid residues (Asp32 and Asp228). Theoretical calculations of the PK values have shown that lupeol could cross the BBB more efficiently than ursolic acid . Moreover, other studies indicated that lupeol have neuroprotective property .…”

“…Another study was performed on Leea indica plant by Hosen et al, where 40 molecules were isolated from different parts of the plant . L .…”

“…81 Another study was performed on Leea indica plant by Hosen et al, where 40 molecules were isolated from different parts of the plant. 82 L. indica is a huge shrub and its leaves were used in folk medicine as antispasmodic, anticancer, and antidiarrheal remedy. 83 Virtual screening studies on the isolated compounds have identified two triterpenes molecules, ursolic acid (compound 27) and lupeol (compound 28) which exhibited higher BACE1 binding affinity.…”

“…Theoretical calculations of the PK values have shown that lupeol could cross the BBB more efficiently than ursolic acid. 82 Moreover, other studies indicated that lupeol have neuroprotective property. 84 It has also been reported that lupeol inhibits BACE1 with an IC 50 value of 5.12 μM.…”