Molecular Docking and Analysis of some Ligands on Var2csA Target

Abstract

Purpose: Prevalence of malaria during pregnancy and the spate of drug resistance by malaria parasites have constantly impacted maternal, perinatal and neonatal outcomes, especially in sub-Saharan Africa. This study aims to discover “in silico” non-recombinant molecules which can interact with placental chondroitin sulfate to inhibit binding or displace bound var2csA from the placenta in order to prevent pregnancy associated malaria.
 Methodology: Protein data bank (rcsb.org) and PubChem were used to download the chemical structures of the receptor (3bqk) and those of the ligands. Canonical SMILES and other information about the ligands and the receptor were extracted from PubChem. Toxtree, Toxicity Estimation Software Tool (TEST), SwissADMET, Molinspiration and Lazar Toxicity Predicter were employed to test various toxicity and safety parameters of lead compounds. The structure of the macromolecule – chondroitin sulfate A (CSA) was retrieved by searching in the protein data bank (PDB) (rcsb.org/structure/3bqk); downloaded, and saved as a PDB format.
 Findings: Molecular modeling and toxicity predictors used in this study indicated that among the ligands screened, IH3 had the lowest binding energy of -9.8Kcal/mol while var2csA had -2.8Kcal/mol. Var2csA is parasite’s adhesive protein. It was also observed that out of the 90 ligands (binding affinity range -9.8 to -1.0 Kcal/mol) screened, IH3 (-9.8Kcal/mol), FAD (-8.4 Kcal/mol), NDP (-8.2 Kcal/mol), A5A (-8.2 Kcal/mol), ABO (-8.1 Kcal/mol), IH2 (-7.8 Kcal/mol), 2RT (-7.7 Kcal/mol), CRO (-7.7 Kcal/mol) and IH1 (-7.7 Kcal/mol) appear to be the most promising lead compounds to occupy var2csA binding pocket in pCSA in order to prevent adhesion of malaria infected erythrocytes to the placenta. SwissADME and Molinspiration Cheminformatics for LogP (mean of 1.07 and range of -2.79 to 4.18) of the lead compounds showed no correlations between lipophilicity and interaction with receptors. Of all the compounds selected for analysis, only ABO and 2RT exhibited drug-like properties based on Ghose, Lipinski and Veber filters.
 Conclusion: Data obtained from the study therefore suggests that IH3, FAD, NDP, A5A, ABO, IH2, 2RT, CRO, IH1 and var2csA make favourable lead candidates for targeting pCSA and therefore require further in vitro and in vivo evaluations.
 Recommendation: This study therefore recommends the repurposing and extending the use of flavin adenine dinucleotide (FAD) to cover prophylactic management of malaria among pregnant women.