MOLECULAR DOCKING AND DYNAMIC SIMULATION OF SEOCALCITOL EFFECTS AGAINST BACE1 TO TREAT ALZHEIMER’S DISEASE

• Main Author: Ulfana Syabila, Baiq
• Format: Theses
• Language: Indonesia
• Subjects: Kimia
• Online Access: https://digilib.itb.ac.id/gdl/view/49590
• Institution: Institut Teknologi Bandung

There were an estimated more than 45 million people worldwide living with dementia in 2015 and this number is will almost triple, reaching 152 million in 2050, makes dementia becoming the greatest burden of global health. Alzheimer's accounts for 60 to 80 percent of dementia cases. One of the most well known hallmark of Alzheimer is the amyloid beta plaque accumulated in the brain. Amyloid beta is a polypeptide and also the byproduct of Amyloid Precursor Protein (APP) hydrolysis process by enzyme called BACE1. Therefore, targeting BACE1 is the main goal in drug discovery for Alzheimer treatment. The aim of this research was to discover a potential compound that exhibit inhibitory effect against BACE1 by skrining virtual method. The candidate compounds came from Vitamin D and its analogues. Seokalsitol, the hit compound from skrining virtual step then analized further its binding stability in complex with BACE1. The study of receptor-ligand stability was performed by molecular dynamic simulation. The compound elenbecestat (ELN) was chosen as a comparator in determining complex stability. The compound with the greatest docking score –9,3 kcal/mol was found to be Seokalsitol (SEO) that form hydrogen bonding with residues Tyr198 and Thr232 in BACE1 active site. Meanwhile for ligan ELN, the docking score was slightly lower –8,9 kcal/mol and form a hydrogen bonding with catalytic residue Asp32. After conducting molecular dynamic simulation for 50 ns, it was showed that hydrogen bond between ligand with residue Tyr198 and Thr232 was unstable, in fact the residue that stabilized ligan SEO in BACE1 active site was Asn37. The same result was found in complex BACE1-ELN where residue Asp32 that was thought before playing role in ligand stabilization turned out to be unstable and replaced by residue Pro70 at the end of simulation. The result from binding energy analysis by MM-GBSA method was quite predictable as the formation of BACE1-SEO complex was more favourable then BACE1- ELN with the value of free binding energy were –43,63 kcal/mol and –22,41 kcal/mol, respectively. The result from free binding energy analysis showed that BACE1-SEO complex is more stable than BACE1-ELN. In conclusion, Seokalsitol is expected to be the leading candidate of BACE1 inhibitor that safer for treatment of Alzheimer Disease.