Identification of potential inhibitors against Inosine 5'-Monophosphate Dehydrogenase of Cryptosporidium parvum through an integrated in silico approach

Abstract

The protozoan parasite Cryptosporidium, found in several vertebrates, including humans, is the source of the global infection known as cryptosporidiosis, which manifests as acute gastroenteritis, abdominal pain, and diarrhea. Although infections in certain individuals have been linked to other species, Cryptosporidium parvum is the main cause of illnesses in humans. Lactate Dehydrogenase, Inosine 5'-Monophosphate Dehydrogenase (IMPDH), and several other targets have been identified by the genome sequencing of C. parvum. Bioactive phytochemicals derived from nature have enormous potential as anti-cryptosporidiosis agents. The study aimed to identify new anti-cryptosporidial agents that work against the IMPDH of the parasite by using integrated in silico approaches. In this study, a total of 24 bioactive phytochemicals were screened virtually through molecular docking and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analyses. Four lead compounds were identified, including Brevelin A (-8.9 kcal/mol), Vernodalin (-8.7 kcal/mol), Luteolin (-8.6 kcal/mol), and Pectolinarigenin (-8.1 kcal/mol), against the IMPDH protein (PDB ID: 4IXH) from the parasite. All the lead compounds had excellent pharmacokinetic and pharmacodynamic characteristics. The toxicity analysis showed satisfactory results with no major side effects. All of the selected compounds showed no violation of Lipinskis rules of five, indicating the possibility of oral bioavailability as potential drug candidates. In the majority of cases, target class prediction-identified enzymes, as well as investigational and experimental drugs, have been found to have structural similarities to the lead compounds. With significant biochemical interactions, all of the targeted phytochemical compounds have demonstrated excellent pharmacokinetics and better bioavailabilities. The findings strongly recommend in vitro experimental studies to aid in the development of novel therapeutics against Cryptosporidium parvum.