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Cellular absorption of small molecules: free energy landscapes of melatonin binding at phospholipid membranes.

ABSTRACT: Free energy calculations are essential to unveil mechanisms at the atomic scale such as binding of small solutes and their translocation across cell membranes, eventually producing cellular absorption. Melatonin regulates biological rhythms and is directly related to carcinogenesis and neurodegenerative disorders. Free energy landscapes obtained from well-tempered metadynamics simulations precisely describe the characteristics of melatonin binding to specific sites in the membrane and reveal the role of cholesterol in free energy barrier crossing. A specific molecular torsional angle and the distance between melatonin and the center of the membrane along the normal to the membrane Z-axis have been considered as suitable reaction coordinates. Free energy barriers between two particular orientations of the molecular structure (folded and extended) have been found to be of about 18?kJ/mol for z-distances of about 1-2?nm. The ability of cholesterol to expel melatonin out of the internal regions of the membrane towards the interface and the external solvent is explained from a free energy perspective. The calculations reported here offer detailed free energy landscapes of melatonin embedded in model cell membranes and reveal microscopic information on its transition between free energy minima, including the location of relevant transition states, and provide clues on the role of cholesterol in the cellular absorption of small molecules.

SUBMITTER: Lu H

PROVIDER: S-EPMC7280225 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Cellular absorption of small molecules: free energy landscapes of melatonin binding at phospholipid membranes.

Lu Huixia H Marti Jordi J

Scientific reports 20200608 1

Free energy calculations are essential to unveil mechanisms at the atomic scale such as binding of small solutes and their translocation across cell membranes, eventually producing cellular absorption. Melatonin regulates biological rhythms and is directly related to carcinogenesis and neurodegenerative disorders. Free energy landscapes obtained from well-tempered metadynamics simulations precisely describe the characteristics of melatonin binding to specific sites in the membrane and reveal the ...[more]

PMID: 32513935

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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

Cellular absorption of small molecules: free energy landscapes of melatonin binding at phospholipid membranes.

Publications

Cellular absorption of small molecules: free energy landscapes of melatonin binding at phospholipid membranes.

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