VIRTUAL SCREENING AND MOLECULAR DYNAMICS SIMULATION OF METABOLITES OF MARINE MICROORGANISM AND ALGAE AS DIHYDROFOLATE REDUCTASE INHIBITOR

• Main Author: Sangande, Frangky
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/45717
• Institution: Institut Teknologi Bandung

Staphylococcus aureus is one of pathogens bacterium that cause nosocomial infection. Trimethoprim is well-known as dihydrofolate reductase (DHFR) inhibitor. It has been recommended for treatment of Staphylococcus aureus infections. However, the emergence of new types of antibiotic-resistant S. aureus, including trimethoprim, should be anticipated by providing more effective antibacterials. Therefore, the aim of the study was to find a new S. aureus DHFR (saDHFR) inhibitors with better activity than trimethoprim. In the present study, structure-based virtual screening targeting saDHFR was performed toward 1,085 secondary metabolites of marine microorganism dan algae using AutoDock Vina and DOCK 6 as docking tools. The test ligands were optimized previously with PM3 method and filtered based on Lipinski’s parameters. Docking procedures were validated based on the value of root mean square deviation (RMSD) and AUC of receiver operating characteristic (ROC) curve. Validation result showed that both of these docking tools met the criteria of RMSD < 2 Å and AUC of ROC curve ?0.7, and could be applied for virtual screening. Initial screening based on Lipinski’s parameters obtained 666 compounds. Further screening through docking simulation, compounds of 2012_351, 2013_376, and 2013_402 were found as potential saDHFR inhibitors. Docking score of these compounds were better than trimethoprim. AutoDock Vina and DOCK 6 score of trimethoprim were –6.4 dan –57.65 respectively. AutoDock Vina score of 2012_351, 2013_376, and 2013_402 were –10.0, –9.2, and –9.4, and their corresponding DOCK 6 score were –76.01, –64.06, and –66.31 respectively. Based on the docking results, the amino acid residues which involved in hydrogen bonding are Gln20, Leu21, Asp28, Ser50, Arg58, Pro56, and Phe93. Further analysis was performed to study molecular dynamics of their complex with saDHFR. According to their binding profile and pharmacophore feature, affinity of these compounds tend to be influenced by hydrophobic interaction. However, although their chemical scaffold are unlike trimethoprim, these compounds were predicted still exhibit inhibitory effect toward F98Y type of trimehtoprim-resistant saDHFR. Moreover, 2013_402 has good complex ligand-enzime stability and exhibits similar mean square displacement MSD profile with trimethoprim. Therefore, 2013_402 is potential as candidate of saDHFR inhibitor.