Modeling antimalarial and antihuman African trypanosomiasis compounds: a ligand- and structure-based approaches
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ORIGINAL ARTICLE
Modeling antimalarial and antihuman African trypanosomiasis compounds: a ligand‑ and structure‑based approaches Jyoti Gahtori1 · Suyash Pant2 · Hemant Kumar Srivastava1 Received: 6 September 2019 / Accepted: 6 November 2019 © Springer Nature Switzerland AG 2019
Abstract This study examines the interaction of 137 antimalarial and antihuman African trypanosomiasis compounds [bis(2-aminoimidazolines), bisguanidinediphenyls and polyamines] on three different in vitro assays (Trypanosoma brucei rhodesiense (T.b.r.), Plasmodium falciparum (P.f.) and cytotoxicity-L6 cells). ΔTm values, wherever available, were also examined for the considered ligands. Eight DNA–ligand complexes and one DNA structure without ligand were selected from protein data bank (PDB) based on the structural similarity. Geometry optimization of all the considered ligands was carried out at the B3LYP/6-31G(d) level of theory. The AutoDock4 tool was utilized for the docking of these molecules at the minor groove of nine selected DNA crystal structures. We observed DT20, DA6, DT8 and DT19 residues generally interact with most of the considered ligands. Molecular dynamics simulations, molecular mechanics–generalized born surface area and molecular mechanics–Poisson Boltzmann surface area calculations indicate that the docked poses are generally stable and docked ligands do not show much deviation in the minor groove of DNA until 10 ns simulation. Efficient and statistically significant quantitative structure–activity relationship models for T.b.r., P.f., C-L6 and ΔTm values were developed. All the generated models are internally and externally validated. We predicted a few ligands with significant IC50 values against P.f. based on the developed models. These results may help to design new and potent antimalarial and antihuman African trypanosomal compounds.
R2 =0.90 R 2 =0.70 R 2 =0.78 R 2 =0.84
50
n=76 n=136 n=71 n=35
>4.0
3.5-4.0
3.0-3.5
0 2.0-3.0
4 3 RMSD 2 1
Descriptors calculation using B3LYP/6 -31G(d) level of DFT
0
PDB IDs 2GYX 102D 2DBE 360D 4U8B 1BNA 298D 3U0U 1FMS
pIC50 (P.f.) Exp.
10
20
30
P.f. T.b.r. C-L6 ΔTm
40
Interacting Residues DT20 DT7 DA17
60
Graphic abstract
pIC 50 (P.f.) Pred.
0
2
4
6 Time (ns)
8
10
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11030-019-10015-y) contains supplementary material, which is available to authorized users. Extended author information available on the last page of the article
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Molecular Diversity
Keywords Trypanosoma brucei rhodesiense · Plasmodium falciparum · Cytotoxicity-L6 · QSAR · Docking · MD simulation
Introduction Humans or alternative life forms on earth are perpetually exposed to parasites and acquire infections frequently. These parasitic maladies dispense significant financial misfortunes to society. As per WHO, more than 3 billion individuals around the globe experience the ill effects of at least one parasitic illness and this is the primary source of grimness and
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