In silico Structure Prediction, Molecular Docking, and Dynamic Simulation of Plasmodium falciparum AP2-I Transcription Factor

Abstract

Plasmodium falciparum Apicomplexan Apetala 2 Invasion ( PfAP2-I) transcription factor (TF) is a protein that regulates the expression of a subset of gene families involved in P. falciparum red blood cell (RBC) invasion. Inhibiting PfAP2-I TF with small molecules represents a potential new antimalarial therapeutic target to combat drug resistance, which this study aims to achieve. The 3D model structure of PfAP2-I was predicted ab initio using ROBETTA prediction tool and was validated using Save server 6.0 and MolProbity. Computed Atlas of Surface Topography of proteins (CASTp) 3.0 was used to predict the active sites of the PfAP2-I modeled structure. Pharmacophore modeling of the control ligand and PfAP2-I modeled structure was carried out using the Pharmit server to obtain several compounds used for molecular docking analysis. Molecular docking and postdocking studies were conducted using AutoDock vina and Discovery studio. The designed ligands’ toxicity predictions and in silico drug-likeness were performed using the SwissADME predictor and OSIRIS Property Explorer. The modeled protein structure from the ROBETTA showed a validation result of 96.827 for ERRAT, 90.2% of the amino acid residues in the most favored region for the Ramachandran plot, and MolProbity score of 1.30 in the 98th percentile. Five (5) best hit compounds from molecular docking analysis were selected based on their binding affinity (between −8.9 and −11.7 Kcal/mol) to the active site of PfAP2-I and were considered for postdocking studies. For the absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties, compound MCULE-7146940834 had the highest drug score (0.63) and drug-likeness (6.76). MCULE-7146940834 maintained a stable conformation within the flexible protein’s active site during simulation. The good, estimated binding energies, drug-likeness, drug score, and molecular dynamics simulation interaction observed for MCULE-7146940834 against PfAP2-I show that MCULE-7146940834 can be considered a lead candidate for PfAP2-I inhibition. Experimental validations should be carried out to ascertain the efficacy of these predicted best hit compounds.

In silico design of peptide inhibitors for Dengue virus to treat Dengue virus-associated infections

“…A total of five models were provided by the PEP-FOLD3 server 26 . The predicted peptide structures were used for validation by the ERRAT and Ramachandran plot analysis 27 . Only the validated model was used for further study.…”

Plasmodial Transcription Factors and Chromatin Modifiers as Drug Targets

“…Five compounds were considered suitable for post-docking studies, with the molecule MCULE-7146940834 being indicated as the main candidate. Experimental preclinical validations are required to assess its effectiveness as an AP2-I inhibitor [94].…”

“…The inferred function and tested druggability of all AP2 factors are resumed in Table 1. Taken together, despite the significant importance of the transcription factors described here for the parasite's development cycle in humans, few studies have been conducted so far using these proteins as targets for new drugs [82,94]. The absence of AP2 domains in humans makes them an attractive target to block the binding of these proteins to DNA or to their mostly unknown cofactors, which may result in profound transcriptional changes and ultimately parasite death.…”