Computer-aided drug discovery using Philippine natural products to target DENV NS5 methyltransferase (MTase)

• Main Authors: Dela Cruz, Malea Corrine Legaspi, Empeynado, Drexelle Marbie Dela Cruz
• Format: text
• Language: English
• Published: Animo Repository 2024
• Subjects: Molecular dynamics; Dengue viruses; Methyltransferases; Natural products > Philippines; Drug development; Chemistry
• Online Access: https://animorepository.dlsu.edu.ph/etdb_chem/47; https://animorepository.dlsu.edu.ph/context/etdb_chem/article/1055/viewcontent/2024_DelaCruz_Empeynado_Computer_aided_drug_discovery_using_Philippine_Natural_Products_t.pdf
• Institution: De La Salle University

The dengue virus (DENV) has been a persistent problem in the Philippines since the 1950s. Despite advances in research, there are no commercially available medications that can effectively inhibit DENV infection. One potential target for drug discovery is the nonstructural protein 5 (NS5), which is highly conserved among the serotypes and plays a crucial role in the virus's pathogenesis and replication. A library of 1,563 Philippine natural products were screened for their ADME properties, resulting in 35 compounds passing the initial screening. Subsequently, docking studies were performed onto the MTase domain in the S-adenosylmethionine (SAM) binding site of the NS5 protein (PDB ID: 5CCV) using the Autodock software. The top three hits were identified as isovanillic acid (C1), longifolene-v4 (C2), and trans-dihydrokaempferol (C3). 100 ns molecular dynamics (MD) simulations were carried out for the apo form and the top protein-ligand complexes using GROMACS-2023.4. It was found that only the NS5-SAH and NS5-C3 complexes remained intact throughout the simulations, attributed to the presence of strong intermolecular forces. Conversely, the complexes involving the C1 and C2 ligands were observed to dissociate in the MD simulation, presumably because of the dissolution of salt bridge and weak intermolecular forces, respectively. The RMSF analysis showed that in chain A, RdRp domain had the highest peaks, encompassing the fingertip domain crucial for catalytic function. In chain B, the most significant fluctuation occurred in the apo form and NS5-C3 complex and is associated with the priming loop that assists viral genome replication. The hydrogen bonding analysis revealed similar interactions between the NS5-SAH and the NS5-C3 complex, particularly at residues ASP146 and GLU111. Additionally, the residue ASP131 exhibited significantly high occupancy specific to NS5-C3. Moreover, the highly negative enthalpy of complex from MM/PB(GB)SA for NS5-SAH and NS5-C3 signifies good stability. Furthermore, the per-residue decomposition highlighted that electrostatic component contributed most with residues ASP146 and ASP131 for NS5-SAH and NS5-C3 complexes, respectively. Overall, the C3 ligand is a promising drug candidate to target the dengue virus due to the strong interaction with key residues, such as ASP131 and ILE147, which are crucial for the MTase domain activity. Likewise, optimizing the top three ligands might enhance the study's findings. Expanding the research with network analysis and principal component analysis (PCA) could offer further insights. Extending the molecular dynamics (MD) run could also facilitate a more comprehensive analysis of the interactions within the protein-ligand complexes. Lastly, calculation of the free binding energy (ΔGbind) can be performed to determine the binding affinity.