Identification of anti-filarial leads against aspartate semialdehyde dehydrogenase of Wolbachia endosymbiont of Brugia malayi: combined molecular docking and molecular dynamics approaches

Abstract

Lymphatic filariasis is a debilitating vector borne parasitic disease that infects human lymphatic system by nematode Brugia malayi. Currently available anti-filarial drugs are effective only on the larval stages of parasite. So far, no effective drugs are available for humans to treat filarial infections. In this regard, aspartate semialdehyde dehydrogenase (ASDase) in lysine biosynthetic pathway from Wolbachia endosymbiont Brugia malayi represents an attractive therapeutic target for the development of novel anti-filarial agents. In this present study, molecular modeling combined with molecular dynamics simulations and structure-based virtual screening were performed to identify potent lead molecules against ASDase. Based on Glide score, toxicity profile, binding affinity and mode of interactions with the ASDase, five potent lead molecules were selected. The molecular docking and dynamics results revealed that the amino acid residues Arg103, Asn133, Cys134, Gln161, Ser164, Lys218, Arg239, His246, and Asn321 plays a crucial role in effective binding of Top leads into the active site of ASDase. The stability of the ASDase-lead complexes was confirmed by running the 30 ns molecular dynamics simulations. The pharmacokinetic properties of the identified lead molecules are in the acceptable range. Furthermore, density functional theory and binding free energy calculations were performed to rank the lead molecules. Thus, the identified lead molecules can be used for the development of anti-filarial agents to combat the pathogenecity of Brugia malayi.

Keywords: ADLA, Acute Dermato-Lymphangio-Adenitis; ADMET, Absorption, Distribution, Metabolism, Excretion and Toxicity; ASDase, aspartate semialdehyde dehydrogenase; BlastP, Basic Local Alignment Search Tool; DFT, Density Functional Theory; GRAVY, Grand Average of Hydropathicity; GROMACS, Groingen Machine for Chemical Simulations; Glide, Grid-based ligand docking with energetic; HOMO, Highest Occupied Molecular Orbital; HTVS, High Throughput Virtual Screening; LUMO, Lowest Unoccupied Molecular Orbital; MD, Molecular Dynamics; MM-GBSA, Molecular Mechanics, The Generalized Born Model and Solvent Accessibility; NPT, Number of particles, Pressure and Temperature; NVT, Number of particles, Volume and Temperature; OPLS-AA, Optimised Potential for Liquid Simulation All Atom; PDB, Brookhaven Protein Databank; PME, Particle-Mesh Ewald; RMSD, Root Mean Square Deviation; RMSF, Root Mean Square Fluctuation; Rg, Radius of gyration; SP, Standard Precision; SPC, Simple Point Charge; WHO, World Health Organization; XP, Extra Precision; aspartate semialdehyde dehydrogenase; density functional theory; lymphatic filariasis; molecular dynamics simulations; pI, iso-electric point; structure-based virtual screening.