POTENTIAL ANALYSIS OF PROPOLIS BIOACTIVE COMPOUNDS AS CANDIDATE FOR ANTIHYPERINFLAMMATION COVID-19 DRUG USING TARGET FISHING APPROACH, MOLECULAR DOCKING AND MOLECULAR DYNAMICS SIMULATION

• Main Author: Marcius, Donny
• Format: Final Project
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/66357
• Institution: Institut Teknologi Bandung

As of June 14th, 2022, the COVID-19 (Corona Virus Disease 2019) pandemic in Indonesia has reached 156,662 death cases. Various clinical data show that hyperinflammatory response is the main cause of patient death. The inflammatory response required by the body to prevents SARS-CoV-2 replicate itself, but an overresponse leads to multiorgan failure and death. Treatment such as antivirals are not active against hyperinflammatory conditions. Studies show the use of synthetic drugs such as tocilizumab and sarilumab provide some adverse effects to patients. On the other hand, the side effects caused by herbal ingredients such as propolis are much lower, as well as the potential to treat complex diseases effectively. The content of propolis compounds varies across bee species and the types of flowers that the bees consumed, in general propolis contains high level of flavonoid compounds and is known to have anti-inflammatory activity. Along with technological developments, the paradigm of drug discovery shifts from hypothesisdriven to data-driven, thus indicates that initial data acquisition research is very important before carrying out further testing stages. The bioinformatics research method used in this final project is target fishing for the prediction of target proteins from flavonoids and their selection to be associated with the COVID-19 hyperinflammatory condition using SARS-CoV-2 DEG data and gene ontology annotations, molecular docking to see the strong bonds formed between protein and ligand complex, and also molecular dynamics simulations to see the stability of the interactions. The results obtained included 96 flavonoid compounds from a total of 124 compounds in the propolis Nano Center Indonesia, 89 of which met Lipinski's rules and 62 had low toxicity properties. Target fishing resulted in the output of 1,105 proteins of which 11 were associated with the hyperinflammatory state of COVID-19. The eleven proteins were: ADA2A, BTK, CCR6, CFAB, E2AK2, MC4R, MMP1, NOS2, NPY5R, PPAP, and STAT1. Based on the results of molecular docking, propolis flavonoid bioactive compounds that meet Lipinski's rules and have low toxicity have potential to become anti-hyperinflammatory drugs candidates because its lower ligand docking score and/or higher and stronger number of interactions than conventional protein inhibitors. These potential compounds in inhibiting BTK protein activity include baicalein-7-O-?-D glucopyranoside with a docking score of ?10.32 kcal/mol and kaempferol-7-O-?- iv L-rhamnoside with a docking score of ?9.45 kcal/mol, in inhibiting CFAB protein activity include 3'-methoxy-puerarin with a docking score of ?8.63 kcal/mol and kaempferol-3-O-rhamnoside with a docking score of ?8.4 kcal/mol, in inhibiting MMP1 protein activity include viscidulin I with a docking score of ?8.27 kcal/mol, and in inhibiting NOS2 protein activity include cosmosiin with a docking score of ?7.48 kcal/mol and apigenin 4'-O-glucoside with a docking score of ?7.16 kcal/mol. Based on the results of molecular dynamics simulations, propolis flavonoid ligands that have strong binding energy and show good stability in interacting with amino acid residues that make up proteins include baicalein-7-O?-D glucopyranoside in inhibiting BTK protein activity through 13 constant interactions at residue Leu408, Gly411, Gln412, Gly414, Ala428, Lys430, Thr474, Glu475, Tyr476, Met477, Gly480, Arg525, and Leu528; kaempferol-3-Orhamnoside in inhibiting CFAB protein activity through 4 constant interactions at residue Tyr99, Pro172D, Cys191, and Trp215; fisetin in inhibiting MMP1 protein activity through 1 constant interaction at residue Glu219; and apigenin 4'-Oglucoside in inhibiting NOS2 protein activity through 1 constant interaction at residue Val352. The conclusion is that the flavonoid compounds in propolis have the potential to become anti-inflammatory drugs candidates because their docking score to the target molecule is lower (negative) compared to conventional inhibitors, the strong type of interactions and bonds, as well as the stability from interactions between proteins and ligands.