MOLECULAR DOCKING STUDY OF ANILINE- AND BENZYLAMINE-SUBSTITUTED PYRAZINE DERIVATIVES COMPOUND AS ANTIBACTERIAL CANDIDATES Zainudin Saputra, Widiastuti Agustina Eko Setyowati
Sebelas Maret University
Abstract
Antibiotic resistance has increased significantly, reducing the effectiveness of treatment for bacterial infections. In 76 countries, the average resistance of Escherichia coli to third-generation cephalosporins reached 42%, while Staphylococcus aureus resistance to methicillin was 35%. S. aureus, Staphylococcus epidermidis, and Methicillin-Resistant Staphylococcus aureus are pathogenic bacteria that frequently cause various infections ranging from mild to severe. Pyrazine is an aromatic heterocyclic compound with potential as an antibacterial framework, but requires structural modification. Substitution of aniline and benzylamine groups was chosen to enhance molecular interactions, binding affinity, and antibacterial activity. This study aims to understand the molecular interactions between pyrazine derivatives substituted with aniline and benzylamine groups with bacterial target proteins of S. aureus, S. epidermidis, and MRSA through molecular docking analysis using Autodock Tools, visualized with Discovery Studio Biovia and pymol, and accompanied by pharmacokinetic and toxicity predictions via the SwissADME and Protox-II websites. The test ligands used were 3-amino-N(4-chlorophenyl)pyrazine-2-carboxamide[1], 3-amino-N-(4-bromophenyl)pyrazine-2-carboxamide[2], 3-amino-N-(4-chlorobenzyl)pyrazine-2-carboxamide[3], 3-amino-N(3 chlorobenzyl)pyrazine-2-carboxamine[4], 3-amino-N-(2,4-dichlorobenzyl)pyrazine-2-carboxamide[5], 3-amino-N-(3-fluorobenzyl)pyrazine-2-carboxamide[6], 3-amino-N-(4-fluorobenzyl)pyrazine-2-carboxamide [7] each targeted at proteins with PDB ID 4CJN (MRSA), 4M8I (S. Epidermidis), and 3G75 (S. aureus). Molecular docking results showed that test ligand 7 had the best affinity for MRSA (-5.6 kcal/mol), test ligand 4 toward S. epidermidis (-7.9 kcal/mol), and test ligand 6 toward S. aureus (-6.7 kcal/mol). All compounds meet Lipinskis and Vebers rules with a bioavailability score of 0.55. Based on these results, it is known that compound 7 for MRSA, 4 for S. epidermidis, and 6 for S. aureus are considered the best drug candidates based on molecular docking exploration and ADMET predictions and are recommended for further testing in vitro and in vivo.
