Design of Novel N-Myristoyltransferase Inhibitors of Leishmania donovani Using Four-Dimensional Quantitative Structure-Activity Relationship Analysis

Abstract

N-Myristoylation protein is catalyzed by N-myristoyltransferase (NMT), an essential target in Leishmania donovani, the causative agent of kala-azar. Four-dimensional quantitative structureactivity relationship (4D-QSAR) analysis was applied to a series of 77 Leishmania donovani NMT inhibitors. Then, three new compounds were proposed using QSAR models. In addition, molecular docking was performed to predict the binding affinities and interaction modes among the proposed compounds and the NMT active site. In silico absorption, distribution, metabolism and excretion (ADME) evaluation was performed and potential inhibitors demonstrated satisfactory pharmacokinetic properties.

Two Decades of 4D-QSAR: A Dying Art or Staging a Comeback?

“…The detailed description of successful applications of RI/RD-4D-QSAR paradigm is beyond the scope of this paper and it can be found elsewhere [ 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 ]. The rough characterization of the scientific projects, where 4D-QSAR methodology was implemented with the specification of the applied protocol, objects of interests and references is reported in Table 1 .…”

RM1 Semiempirical Model: Chemistry, Pharmaceutical Research, Molecular Biology and Materials Science

“…(Amaryllidaceae); 173 C-glucosidic ellagitannins, prepared by a biomimetic synthesis of compound 5-O-desgalloylepipunicacortein A; 187 (5Z)-5-[(5-bromo-1H-indol-3-yl)methylene]-3-(4-chlorobenzyl)-thiazolidine-2,4-dione, which is effective as pan peroxisome proliferatoractivated receptor agonist and cyclooxygenase inhibitor; 189 1,7-bis(aminoalkyl)diazachrysene derivatives, that are capable of inhibiting three unrelated pathogens: the botulinum neurotoxin serotype A light chain; Plasmodium falciparum malaria and Ebola filovirus; 190 derivatives of thiazolidinones with anti-Trypanosoma cruzi activity; 192 derivatives of the E,Z-isomers of 3-arylidene substituted flavanone, chromanone and 3-aryl substituted flavone, that exhibited biological activities for the treatment of the following types of cancer: cell lines (HL-60, NALM-6, WM-115) and normal cell line (HUVEC); 70 2-pyridyl thiazoles, that are anti-Trypanosoma cruzi agents; 193 surfactants of the type bispyridinium diexadecyl cationic gemini, which are nonviral gene-deliveries; 196 phthalimides with antiproliferative and immunomodulatory activities; 202 Aedes aegypti larvicidal based on thiosemicarbazones; 209 inhibitors of chikungunya virus (CHIKV; genus Alphavirus) protease; 210 peroxisome proliferator-activated receptor gamma (PPARγ), which is capable of regulating pathways involved in the pathogenesis of obesity and atherosclerosis; 215 a series of 4-amino-7-chloroquinoline (4,7-ACQ) compounds, that exhibited higher antimalarial activities; 216 usnic acid enamines that enhance the cytotoxic effect of camptothecin, and, therefore, are inhibitors of the tyrosyl-DNA phosphodiesterase; 218 cyclic urea and carbamate derivatives that are α-glucosidase inhibitors; 166 4-aminoquinolines as quorum sensing inhibitors in Serratia marcescens and Pseudomonas aeruginosa; 222 and a set of 77 Leishmania donovani inhibitors of N-myristoyltransferase. 224 Optimized geometries calculated by RM1 were also used as strategy to obtain initial structure for the target systems, to subsequently employ DFT and/or ab initio methods. 169,207,219,221 RM1 was also employed to be compared with these computational methods.…”