Insight into the in Silico Structural, Physicochemical, Pharmacokinetic and Toxicological Properties of Antibacterially Active Viniferins and Viniferin-Based Compounds as Derivatives of Resveratrol Containing a (2,3-Dihydro)benzo[b]furan Privileged Scaffold
Abstract
1. Introduction
- introduction of several chemical aspects related to privileged bicyclic structures containing O-atoms
- in silico characterization of naturally occurring viniferins, their semi-synthetic and synthetic derivatives
- indication of the advantages and limitations of the interactive tools employed
- focusing attention on the advantages and limitations of the analyzed naturally occurring viniferins, their semi-synthetic and synthetic derivatives
2. Some Types of Privileged Bicyclic Structures Present in the Structure of Clinically Approved Drugs and Viniferins
3. Biotransformation of Viniferins
4. Several Aspects of in Silico Evaluation of Some Pharmacologically Notable Natural, Semi-Synthetic, and Synthetic Compounds Containing (Not Only) Various Privileged Scaffolds
4.1. Selected Structural and Physicochemical Properties Which Can Be Effectively Predicted
- pharmacokinetic and biochemical characteristics, that is, ADME indices
- pharmacodynamic properties
- toxicity
4.1.1. Molecular Weight, Stereochemical Properties, Molar Refractivity, Flexibility, Size, Shape, Molecular Volume, and Presence of Heteroatoms in the Structure of Pharmacologically Active Compounds and the Relationships of These Characteristics to PK/PD Properties
4.1.2. Lipohydrophilic Properties, Acid-Base Features, and Solubility of Pharmacologically Active Compounds and the Relationships of These Characteristics to PK/PD Properties
4.2. Selected Toxicological Characteristics Which Can Be Effectively Predicted
4.3. Prediction of Some Parameters That Describe Drug-Likeness
5. Several Notes on Structure–Physicochemical Properties–Antimicrobial Activity Relationships of Viniferins and Viniferin-Based Compounds
5.1. Relationships Between the Structure and Activity of Chosen Viniferins and Viniferin-Based Compounds Against Chosen Gram-Positive Bacterial Strains
5.2. Relationships Between the Predicted Structural, Physicochemical, Pharmacokinetic, and Toxicological Properties of Chosen Viniferins and Viniferin-Based Compounds That Were Very Effective Against Gram-Positive Bacteria
5.2.1. General Overview
- ability to passively permeate via various biological barriers, i.e., SC, intestinal barrier, and the BBB, impact on p-gp (evaluated compounds eventually acting as inhibitors or substrates), and binding to plasma proteins (Table S4);
- inhibitory activity toward respective CYP isoenzymes, i.e., CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, and CYP2B6, and the ability to serve as their substrates (Tables S5 and S6);
- toxicological features, i.e., DILI, H-HT, DINf, HeT, OT, DINe, and impact on an hERG channel in the heart (Tables S7 and S8).
5.2.2. Predicted Structural and Physicochemical Properties of Chosen Viniferins and Viniferin-Based Compounds
- Molecular weight, fraction of sp3 carbon atoms, molecular refractivity, and van der Waals volume
- Hydrogen bonding and lipohydrophilic properties
- Acid-base properties and solubility
5.2.3. Predicted Pharmacokinetic Properties of Chosen Viniferins and Viniferin-Based Compounds
- The passive permeation via stratum corneum
- The passive permeation via other biological barriers
- The impact on P-glycoprotein
- The binding to plasma proteins
R2 = 0.800
- The impact on the cytochrome P450 isoenzymes
5.2.4. Predicted Toxicological Properties of Chosen Viniferins and Viniferin-Based Compounds
R2 = 0.845, |r| = 0.919
6. Pro et Contra Connected with Presently Employed in Silico Tools
7. Conclusions and Future Directions for Viniferins and Viniferin-Based Derivatives
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ADME | Absorption, distribution, metabolism, and excretion |
ALOGPS | Lipophilicity parameter (log P) calculated via a whole-molecule-based ALOGPS method |
BBB | Blood–brain barrier |
CLOGP 4.0 | Lipophilicity parameter (log P) calculated via a fragmental CLOGP 4.0 method |
CNS | Central nervous system |
CV | Cardiovascular |
CYP | Cytochrome P450 |
DILI | Drug-induced liver injury |
DINe | Drug-induced neurotoxicity |
DINf | Drug-induced nephrotoxicity |
FDA | Food and drug administration |
Fsp3 | Fraction of sp3-hybridized carbon atoms |
H-HT | Human hepatotoxicity |
hERG | Human ether-à-gogo-related gene |
HeT | Hematotoxicity |
Kp | Permeability coefficient (in cm/s units) |
log D7.4 | Calculated decadic logarithm of a distribution coefficient (D) at pH = 7.4 |
log Kp | Calculated decadic logarithm of a permeability coefficient (Kp) |
log Peff | Effective intestinal membrane permeability (parameter) |
MCE-18 | Medicinal Chemistry Evolution-18 (parameter) |
miLogP 2.2 | Lipophilicity parameter (log P) calculated via a Molinspiration Cheminformatics’ method based on group contributions |
MLOGP | Lipophilicity parameter (log P) calculated via a Moriguchi’s method |
MR | Molar refractivity (in m3/mol units) |
MW | Molecular weight (in Da units) |
NP(s) | Natural product(s) |
NP score | Natural product score (parameter) |
nC | Number of carbon atoms |
nhet | Number of heteroatoms |
nOHNH | Number of hydrogen-bond donors |
nON | Number of hydrogen-bond acceptors |
nr | Number of rings |
nrigb | Number of rigid bonds |
nrotb | Number of rotatable bonds |
nsc | Number of stereogenic centers |
OT | Ototoxicity |
p-gp | P-glycoprotein |
p-gp-I | Capability to inhibit a P-glycoprotein (parameter) |
p-gp-S | Capability to serve as a substrate for a P-glycoprotein (parameter) |
PC | Principal component |
PCA | Principal component analysis |
PD | Pharmacodynamic(s) |
PK | Pharmacokinetic(s) |
pKa | Acid-base dissociation constant |
PPB | Plasma protein binding (parameter) |
QED | Quantitative estimate of drug-likeness (parameter) |
RSV | Resveratrol |
SC | Stratum corneum |
SMILES | Simplified molecular input line entry system |
tPSA | Topological polar surface area (in A2 units) |
VCCLAB | Virtual computational chemistry laboratory |
VvdW | van der Waals volume (in Å3 units) |
WLOGP | Lipophilicity parameter (log P) calculated via a Wildman and Crippen’s atomic-based method |
XLOGP3 | Lipophilicity parameter (log P) calculated via an atomic/group-based XLOGP3 method |
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Descriptor | Egan et al. [118] | Muegge et al. [119] | Ghose et al. [120] | Oprea [121] |
---|---|---|---|---|
1 MW (Da) | 11 – | 200.00–600.00 | 160.00–480.00 | – |
2 MR (m3/mol) | – | – | 40–130 | – |
3 nrotb | – | ≤15 | – | 2–8 |
4 nr | – | ≤7 | – | 1–4 |
5 nC | – | >4 | – | – |
6 nhet | – | >1 | – | – |
7 nOHNH | – | ≤5 | – | 0–2 |
8 nON | – | ≤10 | – | 2–9 |
9 log P | ≤5.88 | −2.00–5.00 | −0.46–5.60 | – |
10 tPSA (Å2) | ≤131.6 | ≤150.0 | – | – |
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Nádaská, D.; Malík, I. Insight into the in Silico Structural, Physicochemical, Pharmacokinetic and Toxicological Properties of Antibacterially Active Viniferins and Viniferin-Based Compounds as Derivatives of Resveratrol Containing a (2,3-Dihydro)benzo[b]furan Privileged Scaffold. Appl. Sci. 2025, 15, 8350. https://doi.org/10.3390/app15158350
Nádaská D, Malík I. Insight into the in Silico Structural, Physicochemical, Pharmacokinetic and Toxicological Properties of Antibacterially Active Viniferins and Viniferin-Based Compounds as Derivatives of Resveratrol Containing a (2,3-Dihydro)benzo[b]furan Privileged Scaffold. Applied Sciences. 2025; 15(15):8350. https://doi.org/10.3390/app15158350
Chicago/Turabian StyleNádaská, Dominika, and Ivan Malík. 2025. "Insight into the in Silico Structural, Physicochemical, Pharmacokinetic and Toxicological Properties of Antibacterially Active Viniferins and Viniferin-Based Compounds as Derivatives of Resveratrol Containing a (2,3-Dihydro)benzo[b]furan Privileged Scaffold" Applied Sciences 15, no. 15: 8350. https://doi.org/10.3390/app15158350
APA StyleNádaská, D., & Malík, I. (2025). Insight into the in Silico Structural, Physicochemical, Pharmacokinetic and Toxicological Properties of Antibacterially Active Viniferins and Viniferin-Based Compounds as Derivatives of Resveratrol Containing a (2,3-Dihydro)benzo[b]furan Privileged Scaffold. Applied Sciences, 15(15), 8350. https://doi.org/10.3390/app15158350