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Study of the binding mechanism of aptamer to palytoxin by docking and molecular simulation.

ABSTRACT: This paper provides a feasible model for molecular structure analysis and interaction mechanism of aptamer and micromolecule. In this study, modeling and dynamic simulation of ssDNA aptamer (P-18S2) and target (Palytoxin, PTX) were performed separately. Then, the complex structure between DNA and PTX was predicted, and docking results showed that PTX could combine steadily at the groove's top of DNA model by strong hydrogen-bonds and electrostatic interaction. Thus, we truncated and optimized P-18S2 by simulating. At the same time, we also confirmed the reliability of simulation results by experiments. With the experimental and computational results, the study provided a more reasonable interpretation for the high affinity and specific binding of P-18S2 and PTX, which laid the foundation for further optimization and development of aptamers in molecular diagnostics and therapeutic applications.

SUBMITTER: Hu B

PROVIDER: S-EPMC6820544 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Study of the binding mechanism of aptamer to palytoxin by docking and molecular simulation.

Hu Bo B Zhou Rong R Li Zhengang Z Ouyang Shengqun S Li Zhen Z Hu Wei W Wang Lianghua L Jiao Binghua B

Scientific reports 20191029 1

This paper provides a feasible model for molecular structure analysis and interaction mechanism of aptamer and micromolecule. In this study, modeling and dynamic simulation of ssDNA aptamer (P-18S2) and target (Palytoxin, PTX) were performed separately. Then, the complex structure between DNA and PTX was predicted, and docking results showed that PTX could combine steadily at the groove's top of DNA model by strong hydrogen-bonds and electrostatic interaction. Thus, we truncated and optimized P- ...[more]

PMID: 31664144

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Project description:Antimalarial drug resistance has thrown a spanner in the works of malaria elimination. New drugs are required for ancillary support of existing malaria control efforts. Plasmodium falciparum requires host glucose for survival and proliferation. On this basis, P. falciparum hexose transporter 1 (PfHT1) protein involved in hexose permeation is considered a potential drug target. In this study, we tested the antimalarial activity of some compounds against PfHT1 using computational techniques. We performed high throughput virtual screening of 21,352 small-molecule compounds against PfHT1. The stability of the lead compound complexes was evaluated via molecular dynamics (MD) simulation for 100 nanoseconds. We also investigated the pharmacodynamic, pharmacokinetic and physiological characteristics of the compounds in accordance with Lipinksi rules for drug-likeness to bind and inhibit PfHT1. Molecular docking and free binding energy analyses were carried out using Molecular Mechanics with Generalized Born and Surface Area (MMGBSA) solvation to determine the selectivity of the hit compounds for PfHT1 over the human glucose transporter (hGLUT1) orthologue. Five important PfHT1 inhibitors were identified: Hyperoside (CID5281643); avicularin (CID5490064); sylibin (CID5213); harpagoside (CID5481542) and quercetagetin (CID5281680). The compounds formed intermolecular interaction with the binding pocket of the PfHT1 target via conserved amino acid residues (Val314, Gly183, Thr49, Asn52, Gly183, Ser315, Ser317, and Asn48). The MMGBSA analysis of the complexes yielded high free binding energies. Four (CID5281643, CID5490064, CID5213, and CID5481542) of the identified compounds were found to be stable within the PfHT1 binding pocket throughout the 100 nanoseconds simulation run time. The four compounds demonstrated higher affinity for PfHT1 than the human major glucose transporter (hGLUT1). This investigation demonstrates the inhibition potential of sylibin, hyperoside, harpagoside, and avicularin against PfHT1 receptor. Robust preclinical investigations are required to validate the chemotherapeutic properties of the identified compounds.

Dataset Information

Study of the binding mechanism of aptamer to palytoxin by docking and molecular simulation.

Publications

Study of the binding mechanism of aptamer to palytoxin by docking and molecular simulation.

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