Molecular Docking and Dynamics Simulation revealed the Potential Inhibitory Activity of Piomozide against Kynurenine metabolism targeting the Kynurenine 3-monooxygenase

Abstract

Abstract L-tryptophan metabolism depends on the enzyme kynurenine 3-monooxygenase (KMO). Quinolinic acid, kynurenic acid, and other metabolites having consequences for neurology and psychiatry are mostly derived from L-tryptophan. Furthermore, it was shown that hypertension causes an increase in KMO; hence, inhibiting KMO may aid in preventing both hypertension and cardiovascular diseases. In the current investigation, we used in silico techniques to screen for potential KMO inhibitors. SWISS-MODEL was utilized to simulate the homology with full-length rat KMO complexes with a pyrazoyl benzoic acid inhibitor (PDB:6LKD; sequence identity 80.17%) because the previously available human KMO structure (PDB:5X68) was broken. The flexibility of protein structures was predicted using CABS-flex2.0, and Qmean, Errat, and Procheck were used to improve and validate the 3D models. We used receptor-based screening and drug repurposing. The DrugRep virtual screening server was used for high-throughput docking with FDA-approved, FDA-experimental, and traditional Chinese medicine libraries. The lead-like compounds with good pharmacokinetics characteristics, which may have superior stability and affinity for KMO, were discovered to be the top-scoring drugs from the libraries. Pimozide, an approved pharmaceutical, establishes Van der Waals interactions at ARG85 and TYR99, as well as at TYR398 (4.77Å) and ASN363 (3.16Å) for Pi-Hydrophobic and Halogen Fluorine respectively, all of which are important L-kynurenine binding sites. The co-factor FAD binding nearest residue SER53 formed a hydrogen bond interaction (2.89Å). A molecular dynamic simulation of the FDA-approved drug pimozide exhibited greater interactions and affinities for KMO, which may be able to successfully target the KMO. Pimozide is also used as therapy to treat a variety of psychotic effects, neurodegenerative diseases, and hypertension.