Synthesis of Malarial Plasmepsin Inhibitors and Prediction of Binding Modes by Molecular Dynamics Simulations

Abstract

A series of inhibitors of the malarial aspartic proteases Plm I and II have been synthesized with L-mannitol as precursor. These inhibitors are characterized by either a diacylhydrazine or a five-membered oxadiazole ring replacing backbone amide functionalities. Molecular dynamics simulations were applied in the design process. The computationally predicted Plm II Ki values were generally in excellent agreement with the biological results. The diacylhydrazine was found to be superior over the oxadiazole as an amide bond replacement in the Plm I and II inhibitors studied. An extensive flexibility of the S2' pocket was captured by the simulations predicting the binding mode of the unsymmetrical inhibitors. Plm I and II inhibitors with single digit nanomolar Ki values devoid of inhibitory activity toward human Cat D were identified. One compound, lacking amide bonds, was found to be Plm IV selective and very potent, with a Ki value of 35 nM.

Identification of plasmepsin inhibitors as selective anti-malarial agents using ligand based drug design

“…Using Pipeline Pilot, 21 the Wombat ligand database 22 was filtered for all known PM and CatD inhibitors and subsequently supplemented with additional inhibitors to include more recent data. 17,[23][24] This furnished a database of 194 active compounds with activity data (IC 50 and/or K i for the PMs and with additional information, where available for CatD) which was further filtered in order to match the HypoGen requirement for a diverse training set (i. dataset of greater than 16 compounds -this ensures statistical significance of the Ph4 model; ii. activity range of at least 4 orders of magnitude (OM) and each OM be represented by at the least three compounds; iii.…”

In vitro antimicrobial studies of new benzimidazolium salts and silver N-heterocyclic carbene complexes

“…Different pharmacological and biological properties of many heteroaromatic compounds, which are stable, safe, and have biological activity, have been investigated for these two significant applications by different research groups [5][6][7][8][9][10][11][12] . The rapid development of microbial resistance to currently used antibiotics has become a serious healthcare problem 13,14 .…”

Aspartic protease inhibitory and nematocidal activity of phenyl-4-(2-phenylhydrazono)hexahydrofuro[3,2-c]pyridazin-7-ol (Percival dianhydroosazone)

“…Plasmodium species. These enzymes have been identified as potential anti-malarial drug targets 6 , as inhibition of these enzymes could result in malarial parasites death 7,8 . The malarial parasite Plasmodium falciparum aspartic protease plasmepsin-II is involved in hemoglobin degradation during the intra-erythrocyte phase of infection.…”

“…Numerous attempts have been made to design plasmepsin inhibitors to develop novel antimalarial drugs. A wide variety of synthetic and natural plasmepsin inhibitors have been reported [7][8][9][10] . We explored the biological activity of phenyl-4-(2-phenylhydrazono)hexahydrofuro[3,2-c]pyridazin-7-ol formulated as 3, that is available from biomasses by conventional and microwave methods [11][12][13][14] .…”