In Silico Investigation of 4-Hydroxyphenyl-3-nitrobenzoate Derivatives as Potential Inhibitors of Plasmodium falciparum Lactate Dehydrogenase Using Swiss Similarity, Molecular Docking, and ADMET Analysis

Abstract

Malaria remains a major global health challenge due to the increasing resistance of Plasmodium falciparum to existing antimalarial drugs. This study investigated structurally related analogues of 4-hydroxyphenyl-3-nitrobenzoate as potential inhibitors of Plasmodium falciparum lactate dehydrogenase (PfLDH, PDB ID: 1CET) using SwissSimilarity screening, molecular docking, and ADMET analysis. Seven analogues were identified and evaluated alongside chloroquine and lumefantrine as reference compounds. Among the screened compounds, A3, A5, and A4 exhibited stronger binding affinities (−7.7, −7.5, and −7.4 kcal/mol, respectively) than chloroquine (−6.1 kcal/mol) and comparable affinity to lumefantrine (−7.1 kcal/mol). ADMET predictions revealed favorable pharmacokinetic properties for the lead compounds. Furthermore, A3 demonstrated stable binding interactions within the PfLDH active site through hydrogen bonding and hydrophobic interactions. These findings suggest that A3 may serve as a potential lead compound for further experimental evaluation as an antimalarial agent.