#TITLE_ALTERNATIVE#

• Main Author: ACHSENDO YUNIARTA (NIM : 20715025), TEGAR
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/24495
• Institution: Institut Teknologi Bandung

Malaria is one of the most life threatening infectious disease in the world. Febrifugine, one of the chemical constituents found in Dichroa febrifuga, has long been known to exhibit potent activity against malaria. However, strong toxicity has precluded its usage as a clinical drug. Several derivatization strategies have been attempted in order to obtain new analogues which have better activity and toxicity profile. Recent studies suggest that febrifugine and its derivatives (e.g. halofuginone) act via inhibition of Prolyl-tRNA Synthetase enzyme in Plasmodium falciparum. This research aims to identify compounds which are presumed to possess inhibitory activity against PfPRS by in silico design. Initially, pharmacophore model was built based on febrifugine and its derivatives which have been proven to inhibit PfPRS. The best model obtained was then employed to screen over 6 million compounds in MolPort database. Subsequently, the result from this step was filtered with respect to drug-likeness (Rule of Five, Veber Rule, and number of aromatic ring), then followed by removal of compounds containing PAINS (Pan Assay Interference Compounds) and toxicophore substructure. Two stages molecular docking (rigid receptor docking and induced-fit docking) were then performed against the enzyme (PDB ID: 4YDQ). In addition, PLIF (Protein-Ligand Interaction Fingerprint) method was used as the post-processing filter of docking poses obtained from the latter stage of molecular docking. This approach has led to a discovery of two novel compounds (MolPort 000-427-282 & MolPort 023-290-291), which has better docking score than halofuginone. Based on molecular dynamics simulation for 20 ns, both of those compounds displayed stability in ligand-protein complex.