Docking, QM/MM, and molecular dynamics simulations of the hexose transporter from Plasmodium falciparum (PfHT)

Fonseca, Amanda Luisa da; Nunes, Renata Rachide; Braga, Vanildo Martins Lima; Comar, Moacyr; Alves, Ricardo José; Varotti, Fernando de Pilla; Taranto, Alex Gutterres

doi:10.1016/j.jmgm.2016.03.015

Cited by 18 publications

(17 citation statements)

References 72 publications

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“…These residues play important roles as they interact with ligands as hydrogen donor, hydrogen acceptor, and pi-pi interaction. Fonseca et al [38] reported similar amino acids as essential residues in the binding pocket of Pf HT1. The pi-pi interactions in most of the complexes are formed by Asn48, Asn52, Asn318, and Ser317.…”

Section: Discussionmentioning

confidence: 99%

Molecular docking, simulation and binding free energy analysis of small molecules as PfHT1 inhibitors

Owoloye

Ligali

Enejoh

et al. 2022

Preprint

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Malaria chemotherapy has been plagued by parasite resistance. Novel drugs must be continually explored for malaria treatment. Plasmodium falciparum requires host glucose for survival and proliferation. Protein involved in hexose permeation, P. falciparum hexose transporter 1 (PfHT1) is a potential drug target. 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 Generalised 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 compounds were identified: Hyperoside (CID5281643); avicularin (CID5490064); sylibin (CID5213); harpagoside (CID5481542) and quercetagetin (CID5281680). The compounds formed intermolecular interaction with the binding pocket of the 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.

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Section: Discussionmentioning

confidence: 99%

Molecular docking, simulation and binding free energy analysis of small molecules as PfHT1 inhibitors

Owoloye

Ligali

Enejoh

et al. 2022

Preprint

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“…In addition, the molecular targets P. falciparum ATPase calcium pump ortholog (PfATP6) and hexose transporter P. falciparum (PfHT) were constructed by comparative modeling. 15 , 16 …”

Section: Methodsmentioning

confidence: 99%

Brazilian malaria molecular targets (BraMMT): selected receptors for virtual high-throughput screening experiments

Nunes

Fonseca

Pinto

et al. 2019

Mem. Inst. Oswaldo Cruz

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BACKGROUND Owing to increased spending on pharmaceuticals since 2010, discussions about rising costs for the development of new medical technologies have been focused on the pharmaceutical industry. Computational techniques have been developed to reduce costs associated with new drug development. Among these techniques, virtual high-throughput screening (vHTS) can contribute to the drug discovery process by providing tools to search for new drugs with the ability to bind a specific molecular target. OBJECTIVES In this context, Brazilian malaria molecular targets (BraMMT) was generated to execute vHTS experiments on selected molecular targets of Plasmodium falciparum . METHODS In this study, 35 molecular targets of P. falciparum were built and evaluated against known antimalarial compounds. FINDINGS As a result, it could predict the correct molecular target of market drugs, such as artemisinin. In addition, our findings suggested a new pharmacological mechanism for quinine, which includes inhibition of falcipain-II and a potential new antimalarial candidate, clioquinol. MAIN CONCLUSIONS The BraMMT is available to perform vHTS experiments using OCTOPUS or Raccoon software to improve the search for new antimalarial compounds. It can be retrieved from www.drugdiscovery.com.br or download of Supplementary data.

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“…Therefore, it is necessary to do a combination study with dynamic molecular simulation to obtain more reliable data for studying the candidate's binding free energy with the receptor. 47,48 The binding of the nordentatin derivatives as a cAMP pathway inhibitor can be predicted based on the stability and types of interactions that occur at the molecular level. This can help us understand the mechanism of the interaction that occurs between the candidate and the receptor.…”

Section: Candidate-receptor Interactions At the Molecular Levelmentioning

confidence: 99%

In silicoapproach: biological prediction of nordentatin derivatives as anticancer agent inhibitors in the cAMP pathway

et al. 2020

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Docking, QM/MM, and molecular dynamics simulations of the hexose transporter from Plasmodium falciparum (PfHT)

Cited by 18 publications

References 72 publications

Molecular docking, simulation and binding free energy analysis of small molecules as PfHT1 inhibitors

Molecular docking, simulation and binding free energy analysis of small molecules as PfHT1 inhibitors

Brazilian malaria molecular targets (BraMMT): selected receptors for virtual high-throughput screening experiments

In silicoapproach: biological prediction of nordentatin derivatives as anticancer agent inhibitors in the cAMP pathway

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