South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches

Abstract

The hemoglobin degradation process in Plasmodium parasites is vital for nutrient acquisition required for their growth and proliferation. In P. falciparum, falcipains (FP-2 and FP-3) are the major hemoglobinases, and remain attractive antimalarial drug targets. Other Plasmodium species also possess highly homologous proteins to FP-2 and FP-3. Although several inhibitors have been designed against these proteins, none has been commercialized due to associated toxicity on human cathepsins (Cat-K, Cat-L and Cat-S). Despite the two enzyme groups sharing a common structural fold and catalytic mechanism, distinct active site variations have been identified, and can be exploited for drug development. Here, we utilize in silico approaches to screen 628 compounds from the South African natural sources to identify potential hits that can selectively inhibit the plasmodial proteases. Using docking studies, seven abietane diterpenoids, binding strongly to the plasmodial proteases, and three additional analogs from PubChem were identified. Important residues involved in ligand stabilization were identified for all potential hits through binding pose analysis and their energetic contribution determined by binding free energy calculations. The identified compounds present important scaffolds that could be further developed as plasmodial protease inhibitors. Previous laboratory assays showed the effect of the seven diterpenoids as antimalarials. Here, for the first time, we demonstrate that their possible mechanism of action could be by interacting with falcipains and their plasmodial homologs. Dynamic residue network (DRN) analysis on the plasmodial proteases identified functionally important residues, including a region with high betweenness centrality, which had previously been proposed as a potential allosteric site in FP-2.

Allosteric pockets and dynamic residue network hubs of falcipain 2 in mutations including those linked to artemisinin resistance

“…These sites were found to correlate closely with known functional sites, demonstrating how BC analysis may be utilized to identify functional sites on a protein [97] . In a previous study, BC was successfully used to identify key residues in FPs and how ligand binding on the orthosteric site affected the communication network around the active site, as well as distal sites [98] . Similar studies have also applied BC to identify potential allosteric sites and mutation-induced changes in a range of protein systems [38] , [95] , [97] , [99] .…”

SANCDB: an update on South African natural compounds and their readily available analogs

“…Analog information is important during hit optimization in drug discovery process. Screening hits identified from SANCDB can be further optimized through their analogs [ 13 , 16 , 17 , 19 , 83 ]. Additionally, more potent analogs of the potential allosteric modulators identified in SANCDB [ 14 , 15 , 84 ] may further enhance allosteric modulation of these compounds on their targets.…”

Characterisation of plasmodial transketolases and identification of potential inhibitors: an in silico study

“…5 and Table 2 ). A significant principle in early drug development is decreasing drug failure rate by early identification and elimination of hits that consist of unfavorable structural and physicochemical properties that may result in reduced bioavailability and toxicity [ 75 , 76 ]. Therefore, analysis to determine the drug-likeness of the identified hits was performed using the Lipinski RO5 and PAIN filtering.…”