Ligand-based Pharmacophore Modeling and Molecular

Docking Studies of Akt2 Inhibitors from

Marine Natural Product Database
Zenith Putri Dewianti 1,2, Elin Julianti1*, Sophi Damayanti1
1
School of Pharmacy, Bandung Institute of Technology, Bandung, Indonesia
2
Faculty of Pharmacy, University of Muhammadiyah A.R. Fachruddin, Tangerang, Indonesia

* Corresponding author.
E-mail: elin_julianti@itb.ac.id

Keywords: Ligand-based pharmacophore, virtual screening, docking, Akt2 inhibitors,

Marine Natural Product

Background
The mechanism of adaptation of cancer cells nutrient-starved conditions has recently
become the center of attention as a possible therapeutic target. The protein kinase Akt is a
central signaling molecule within the PI3K/Akt/mTOR pathway. It phosphorylates and
regulates the function of many cellular proteins involved in processes that include
metabolism, apoptosis, and proliferation. Dysregulated activation of Akt2 has been
implicated in several types of cancer. This research aimed to discover potential compounds
as Akt2 inhibitors by in silico studies. This is part of exploration in studying the cytotoxic
activity of Marine Natural Products, especially PANC-1.

Methods
The pharmacophore model of Akt2 was generated and validated to screen the compounds
from the comprehensive marine natural products database. Hit compounds from the
pharmacophore screening were then subjected to molecular docking. Top five hit
compounds were searched for their identity and origin, than visualized for their interaction
with Akt2.

Results
AUC 100% of internal and external validation is 0.77 and 0.80, respectively. The root-mean-
square deviation (RMSD) of redocking native ligan 4-amino-N-(4-chlorobenzyl)-1-(7H-
pyrolo[2,3-D]pyrimidin-4-YL)piperidine-4-carboxamide is 0.7605 Å . Pharmacophore
screening yielded 442 hit compounds from a total of 47451 databases. It showed that 216
compounds has lower docking scores and stable binding interaction with Akt2 compared to
native ligan. The five best compounds, such as aerophobin 1 (Mediterranean sea),
trypargimine (Indonesia, Selat Makassar), 1-carboxytrypargine (Indonesia, Selat Makassar),
aerophobin 1 (Italy), and aerophobin 2 (Italy) have 7, 9, 7, 8, and 16 poses interaction with
amino acid residues, respectively.

Conclusions
Marine natural product has a promising potential as Akt2 inhibitor. The in silico studies
provide insights to the development of novel anti-austerity agents and can be continued with
molecular dynamics simulations.