Discovery of novel antifungal drugs through the inhibition of the Shikimate pathway

• Main Author: T Niraj
• Other Authors: Mu Yuguang
• Format: Final Year Project
• Language: English
• Published: Nanyang Technological University 2023
• Subjects: Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/167013
• Institution: Nanyang Technological University

Fungal infections kill over a million people annually. Current anti-fungal agents have multiple limitations such as resistance and toxicity. Therefore, it is paramount for the swift and accurate discovery of new antifungal drugs. Computer Aided Drug Discovery allows for effective drug discovery via techniques such as molecular dynamics (MD) simulations. There are little studies on the Shikimate Pathway, a vital process in fungi for the formation of aromatic compounds, as a potential target for drugs. This study looks at the first enzyme of the pathway, DAHP Synthase (DAHPS), as the target for inactivation in the Malassezia species. The Malassezia DAHPS sequence was derived using BLAST. MD simulations were carried out for DAHPS using GROMACS. Docking was performed in AutoDock Vina using an FDA-approved library of 2115 ligands and the top-ranked ligand was selected – Ligand 2091. Hydrogen bond analysis and an MD simulation were carried out for the DAHPS-Ligand 2091 complex. Fluctuations in stability were observed for the DAHPS enzyme and the complex, attributing to the poor characterisation of the Malassezia DAHPS. Strong hydrogen bond interactions were identified between Ligand 2091 and the DAHPS binding pocket. Further research is needed to derive the accurate sequence and structure of the Malassezia DAHPS.