Abstract
BackgroundEmergence of cross-resistance to current anti-malarial drugs has led to an urgent need for identification of potential compounds with novel modes of action and anti-malarial activity against the resistant strains. One of the most promising therapeutic targets of anti-malarial agents related to food vacuole of malaria parasite is haemozoin, a product formed by the parasite through haemoglobin degradation.MethodsWith this in mind, this study developed two-dimensional-quantitative structure–activity relationships (QSAR) models of a series of 21 haemozoin inhibitors to explore the useful physicochemical parameters of the active compounds for estimation of anti-malarial activities. The 2D-QSAR model with good statistical quality using partial least square method was generated after removing the outliers.ResultsFive two-dimensional descriptors of the training set were selected: atom count (a_ICM); adjacency and distance matrix descriptor (GCUT_SLOGP_2: the third GCUT descriptor using atomic contribution to logP); average total charge sum (h_pavgQ) in pKa prediction (pH = 7); a very low negative partial charge, including aromatic carbons which have a heteroatom-substitution in “ortho” position (PEOE_VSA-0) and molecular descriptor (rsynth: estimating the synthesizability of molecules as the fraction of heavy atoms that can be traced back to starting material fragments resulting from retrosynthetic rules), respectively. The model suggests that the anti-malarial activity of haemozoin inhibitors increases with molecules that have higher average total charge sum in pKa prediction (pH = 7). QSAR model also highlights that the descriptor using atomic contribution to logP or the distance matrix descriptor (GCUT_SLOGP_2), and structural component of the molecules, including topological descriptors does make for better anti-malarial activity.ConclusionsThe model is capable of predicting the anti-malarial activities of anti-haemozoin compounds. In addition, the selected molecular descriptors in this QSAR model are helpful in designing more efficient compounds against the P. falciparum 3D7A strain.
Highlights
Emergence of cross-resistance to current anti-malarial drugs has led to an urgent need for identification of potential compounds with novel modes of action and anti-malarial activity against the resistant strains
To conduct this study, database of 21 anti-haemozoin compounds was taken for building 2D-quantitative structure–activity relationships (QSAR) models (Table 1) to explore the structure–activity relationship of haemozoin inhibitors acting as anti-malarial agents
These compounds had in vitro anti-malarial activities against P. falciparum 3D7A and were used for QSAR modelling
Summary
Emergence of cross-resistance to current anti-malarial drugs has led to an urgent need for identification of potential compounds with novel modes of action and anti-malarial activity against the resistant strains. The disease is caused by the bite of a mosquito having the Plasmodium parasite, which consists of five main species, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium knowlesi and Plasmodium malariae [2]. Of these species, 90% of deaths (mostly in children) were related to P. falciparum [3]. Plasmodium species developed resistance to most of these commonly used drugs. This resistance and the lack of a vaccine has become a major problem in malarial treatment in recent years [7]. There is a pressing need to improve the efficiency by modifying existing compounds to face drug-resistance, as well as to discover novel anti-malarial compounds
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