Prediction of the permeability of neutral drugs inferred from their solvation properties

Milanetti, Edoardo; Raimondo, Domenico; Tramontano, Anna

doi:10.1093/bioinformatics/btv725

Cited by 23 publications

(15 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This method presents several advantages over previously developed computational and experimental approaches: it is sensitive to the specific environment of the amino acids and can be applied to unnatural and modified amino acids, as well as to other small organic molecules (Bonella et al, 2014;Leopizzi et al, 2017). In particular, analyzing the structural changes of the dynamic hydrogen bond network, we studied both the trans-membrane passive permeation properties for a set of neutral drugs (Milanetti et al, 2016) and the properties of nonsteroidal anti-inflammatory drugs to predict the extraction recovery of NSAIDs from biological fluids set by solid-phase extraction (Milanetti et al, 2019). When amino acids solvation properties are studied, the main limitation of this method relied on considering a single amino acid in solution instead of inserting it in a functional protein chain.…”

Section: Introductionmentioning

confidence: 99%

Characterizing Hydropathy of Amino Acid Side Chain in a Protein Environment by Investigating the Structural Changes of Water Molecules Network

Rienzo

Miotto

Bò

et al. 2021

Front. Mol. Biosci.

Self Cite

View full text Add to dashboard Cite

Assessing the hydropathy properties of molecules, like proteins and chemical compounds, has a crucial role in many fields of computational biology, such as drug design, biomolecular interaction, and folding prediction. Over the past decades, many descriptors were devised to evaluate the hydrophobicity of side chains. In this field, recently we likewise have developed a computational method, based on molecular dynamics data, for the investigation of the hydrophilicity and hydrophobicity features of the 20 natural amino acids, analyzing the changes occurring in the hydrogen bond network of water molecules surrounding each given compound. The local environment of each residue is complex and depends on the chemical nature of the side chain and the location in the protein. Here, we characterize the solvation properties of each amino acid side chain in the protein environment by considering its spatial reorganization in the protein local structure, so that the computational evaluation of differences in terms of hydropathy profiles in different structural and dynamical conditions can be brought to bear. A set of atomistic molecular dynamics simulations have been used to characterize the dynamic hydrogen bond network at the interface between protein and solvent, from which we map out the local hydrophobicity and hydrophilicity of amino acid residues.

show abstract

Section: Introductionmentioning

confidence: 99%

Characterizing Hydropathy of Amino Acid Side Chain in a Protein Environment by Investigating the Structural Changes of Water Molecules Network

Rienzo

Miotto

Bò

et al. 2021

Front. Mol. Biosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, RA‐pro had inhibitory effects similar to tannic acid against P. chibensis and S. warneri. Normally, higher hydrophobicity of active substances increases the permeability of the cell membrane of bacteria (Fujikawa, Nakao, Shimizu, & Akamatsu, ; Milanetti, Raimondo, & Tramontano, ). The effects of RA‐pro were always greater than RA‐hex against these three bacteria.…”

Section: Resultsmentioning

confidence: 99%

Rosmarinic acid and its ester derivatives for enhancing antibacterial, α-glucosidase inhibitory, and lipid accumulation suppression activities

et al. 2018

View full text Add to dashboard Cite

Rosmarinic acid (RA), commonly found in Nepetoidae subfamily of Lamiaceae family, possesses various biological activities. To expand its application, RA was modified by esterification with methyl (me), propyl (pro), and hexyl (hex) alcohols and then tested antibacterial, α‐glucosidase inhibitory, and lipid accumulation suppression activities. Consequently, RA derivatives enhanced antibacterial activity, especially the RA‐pro and RA‐hex, which effectively inhibited the growth of Bacillus cereus rather than tannic acid, a natural antibacterial agent. RA‐hex also inhibited α‐glucosidase inhibitory activity greater than luteolin. By computational molecular docking, dihydroxyphenyl group and hexyl group were selected as essential groups for interaction with the active site of α‐glucosidase through hydrogen bonding and hydrophobic interaction, contributing to the great inhibitory activity. Furthermore, RA‐pro and RA‐hex effectively suppressed lipid accumulation of 3T3‐L1 cells, superior to EGCG, a well‐known anti‐obesity phytochemical. These biological effects of RA derivatives commonly attributed to hydrophobicity, hydrogen bonding, and steric bulkiness of the side chain. Practical applications Rosmarinic acid (RA), a fundamental compound in the family Lamiaceae, is one of powerful naturally occurring antioxidants as well as other biological activities. Furthermore, its abundance in nature was also high in amount in the plant kingdom. So, natural RA can be one of possible natural resources for creating potent natural drugs and biologically useful substances after chemical modification. Studies on various biological activities may intensively expand usage and application of RA. In this study, RA was derivatized to corresponding ester such as methyl, propyl, and hexyl alcohols with higher hydrophobicity, and found great antibacterial, α‐glucosidase inhibitory, and lipid accumulation suppression activities. RA‐pro and RA‐hex significantly suppressed lipid accumulation and cell differentiation. Therefore, RA derivatives with multiple biological activities have the potential to be applied in the food and pharmaceutical industries as food ingredients and supplements.

show abstract

“…In order for RyR2 to be a clinically useful target for phenytoin, it would need to be able to readily diffuse across the sarcolemma to reach to the sarcoplasmic reticulum membrane (Milanetti et al, 2016), and it would need to inhibit RyR2 channels with concentrations below those which produce toxic inhibition of other ion channels and transporters. The Caco-2 (human colon adenocarcinoma) cell monolayer is widely used for the determination of drug intestinal permeability and absorption (Patil et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…The Caco-2 (human colon adenocarcinoma) cell monolayer is widely used for the determination of drug intestinal permeability and absorption (Patil et al, 2012). This assay reveals phenytoin to be a highly membrane-permeable drug (Pade and Stavchansky, 1998;Milanetti et al, 2016), which should readily access RyR2 channels in muscle. We show that phenytoin inhibits RyR2 with an IC 50 ∼15 mM, which is substantially lower than its IC 50 for other muscle ion transporters, such as Na 1 channels [IC 50 5 58 mM (Pincus and Lee, 1973;Yaari et al, 1986;Lang et al, 1993)] and L-type and T-type Ca 12 channels [IC 50 ∼100-200 mM (Hasbani et al, 1974;Yatani et al, 1986;Twombly et al, 1988)].…”

Section: Discussionmentioning

confidence: 99%

Phenytoin Reduces Activity of Cardiac Ryanodine Receptor 2; A Potential Mechanism for Its Cardioprotective Action

et al. 2020

View full text Add to dashboard Cite

Phenytoin is a hydantoin derivative that is used clinically for the treatment of epilepsy and has been reported to have antiarrhythmic actions on the heart. In a failing heart, the elevated diastolic Ca 21 leak from the sarcoplasmic reticulum can be normalized by the cardiac ryanodine receptor 2 (RyR2) inhibitor, dantrolene, without inhibiting Ca 21 release during systole or affecting Ca 21 release in normal healthy hearts. Unfortunately, dantrolene is hepatotoxic and unsuitable for chronic long-term administration. Because phenytoin and dantrolene belong to the hydantoin class of compounds, we test the hypothesis that dantrolene and phenytoin have similar inhibitory effects on RyR2 using a single-channel recording of RyR2 activity in artificial lipid bilayers. Phenytoin produced a reversible inhibition of RyR2 channels from sheep and human failing hearts. It followed a hyperbolic dose response with maximal inhibition of ∼50%, Hill coefficient ∼1, and IC 50 ranging from 10 to 20 mM. It caused inhibition at diastolic cytoplasmic [Ca 21 ] but not at Ca 21 levels in the dyadic cleft during systole. Notably, phenytoin inhibits RyR2 from failing human heart but not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans. We conclude that phenytoin could effectively inhibit RyR2-mediated release of Ca 21 in a manner paralleling that of dantrolene. Moreover, the IC 50 of phenytoin in RyR2 is at least threefold lower than for other ion channels and clinically used serum levels, pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrythmias. SIGNIFICANCE STATEMENTWe show that phenytoin, a Na channel blocker used clinically for treatment of epilepsy, is a diastolic inhibitor of cardiac calcium release channels [cardiac ryanodine receptor 2 (RyR2)] at doses threefold lower than its current therapeutic levels. Phenytoin inhibits RyR2 from failing human heart and not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans and pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrhythmias.

show abstract

Prediction of the permeability of neutral drugs inferred from their solvation properties

Cited by 23 publications

References 60 publications

Characterizing Hydropathy of Amino Acid Side Chain in a Protein Environment by Investigating the Structural Changes of Water Molecules Network

Characterizing Hydropathy of Amino Acid Side Chain in a Protein Environment by Investigating the Structural Changes of Water Molecules Network

Rosmarinic acid and its ester derivatives for enhancing antibacterial, α-glucosidase inhibitory, and lipid accumulation suppression activities

Phenytoin Reduces Activity of Cardiac Ryanodine Receptor 2; A Potential Mechanism for Its Cardioprotective Action

Contact Info

Product

Resources

About