Identification of adaptive inhibitors of Cryptosporidium parvum fatty acyl-coenzyme A synthetase isoforms by virtual screening
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Cryptosporidiosis is a significant cause of gastroenteritis in both humans and livestock in developing countries. The only FDA-approved drug available against the same is nitazoxanide, with questionable efficacy in malnourished children and immunocompromised patients. Recent in vitro studies have indicated the viability of Triacsin C as a potential drug candidate, which targets the parasite’s long-chain fatty acyl coenzyme A synthetase enzyme (LC-FACS), a critical component of the fatty acid metabolism pathway. We have used this molecule as a baseline to propose more potent versions thereof. We have applied a combined approach of substructure replacement, literature search, and database screening to come up with 514 analogs of Triacsin C. A virtual screening protocol was carried out which lead us to identify a potential hit compound. This was further subjected to a 100-ns molecular dynamics simulation in complex to determine its stability and binding characteristics. After which, the ADME/tox properties were predicted to assess its viability as a drug. The molecule R134 was identified as the best hit due to its highest average binding affinity, stability in complex when subjected to MD simulations, and reasonable predicted ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties comparable to those of the Triacsin C parent molecule. We have proposed R134 as a putative drug candidate against the Cryptosporidium parvum LC-FACS enzyme isoforms, following an in silico protocol. We hope the results will be helpful when planning future in vitro experiments for identifying drugs against Cryptosporidium.
KeywordsCryptosporidium Fatty acyl coenzyme A synthetase Cheminformatics Virtual screening Molecular dynamics simulation
The authors would like to acknowledge the Bioinformatics Lab Facility of School of Biotechnology, KIIT deemed to be university during the course of the study. The authors would like to thank Dr. Nivedita Jena of KIIT TBI (Technology Business Incubator) for her proposal of the structure of the MCD1 molecule.
- Guo, F., 2014. Long chain fatty acyl-coenzyme A synthetase as novel drug targets in Cryptosporidium parvum (doctoral dissertation)Google Scholar
- Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461Google Scholar
- Wanyiri J, Ward H (2006) Molecular basis of Cryptosporidium–host cell interactions: recent advances and future prospects. Future Med 1:201–208Google Scholar
- Yang H, Lou C, Sun L, Li J, Cai Y, Wang Z et al (2019) admetSAR 2.0: web-service for prediction and optimization of chemical ADMET properties. Bioinformatics 35(6):1067–1069Google Scholar