Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches

Abstract

The biomineral haemozoin, or its synthetic analogue β-haematin (βH), has been the focus of several target-based screens for activity against Plasmodium falciparum parasites. Together with the known βH crystal structure, the availability of this screening data makes the target amenable to both structure-based and ligand-based virtual screening. In this study, molecular docking and machine learning techniques, including Bayesian and support vector machine classifiers, were used in sequence to screen the in silico ChemDiv 300k Representative Compounds library for inhibitors of βH with retained activity against P. falciparum. We commercially obtained and tested a prioritised set of inhibitors and identified the coumarin and iminodipyridinopyrimidine chemotypes as potent in vitro inhibitors of βH and whole cell parasite growth.

A quantum mechanics and molecular mechanics study of bis-thiosemicarbazones with strong antiplasmodial properties as Fe(iii)-selective chelators and inhibitors of hemozoin formation

“…This crystal face selectivity by L1–L4 is attributable to the corrugations or grooves in the (001) surface which allow access to the propionyl groups and aromatic rings of its constituent β-hematin dimers, which are available for π-stacking and hydrogen bonding interactions, respectively. 49 This makes the (001) face of βHM the most efficient surface for crystal growth-inhibition. This observation is similar to that made in some previous studies in this regard, 2,49 which investigated the βHM crystal-growth inhibition by some organic antimalarials.…”

“…49 This makes the (001) face of βHM the most efficient surface for crystal growth-inhibition. This observation is similar to that made in some previous studies in this regard, 2,49 which investigated the βHM crystal-growth inhibition by some organic antimalarials.…”

“…The fast-growing (001) surface of the bHM crystal is the primary target of antimalarial drugs that exert their therapeutic effects by preventing free heme detoxification in plasmodia via inhibition of hemozoin formation. 2,49 It can be seen from the values in Table 5 that whatever the crystal surface available for adsorption, L3 and L4 are the strongest bHM binders. Owing to their relatively high binding affinities to the (001) crystal face, L3 and L4 are most likely to significantly inhibit the growth of b-hematin crystals by surface poisoning of its (001) face.…”

In silico discovery of potential sodium–glucose cotransporter-2 inhibitors from natural products for Prevent Kidney Failure in Patients with Type 2 Diabetes

“…Then obtained pharmacophore was searched in the mentioned database using the MOE program (http://www.chemcomp.com), and only 1,336 of the 114,313 natural compounds in the library were extracted. Following a virtual screening using the PyRx program 42,43 , ve compounds were selected due to having the lowest binding energy (about -10 kcal/mol) and the hydrogen binding number to the active site compared to the standard ligand (empagli ozin). The pharmacokinetic properties of the six desired compounds were investigated along with the standard drug empagli ozin and three approved drugs (canagli ozin, dapagli ozin, and ertugli ozin) using programs the Schrödinger (Schrodinger Release 2021.2: QikProp, Schrodinger, LLC, New York, NY, 2021) and SwissADME [44][45][46][47] , that only two compounds (306 and 580) were in range for 95% known drugs.…”