Practical High-Quality Electrostatic Potential Surfaces for Drug Discovery Using a Graph-Convolutional Deep Neural Network

Rathi, Prakash Chandra; Ludlow, R. Frederick; Verdonk, Marcel L.

doi:10.1021/acs.jmedchem.9b01129

Cited by 100 publications

(83 citation statements)

References 37 publications

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“…The molecular electrostatic potential (MEP) of the top hit compound was also plotted over the compounds' electronic structure from the DFT calculation. The observed MEP surface around a compound by the charge distribution provides information about the reactive sites for the nucleophilic and electrophilic attack in hydrogen bonding interactions [ 29 ] and other processes requiring biological recognition [ 30 ]. The MEP for the top hit compounds shows the electrophilic region and the nucleophilic region.…”

Section: Resultsmentioning

confidence: 99%

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

Adelusi

Abdul-Hammed

Idris

et al. 2021

Heliyon

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Inhibitors of Keap1 would disrupt the covalent interaction between Keap1 and Nrf2 to unleash Nrf2 transcriptional machinery that orchestrates its cellular antioxidant, cytoprotective and detoxification processes thereby, protecting the cells against oxidative stress mediated diseases. In this in silico research, we investigated the Keap1 inhibiting potential of fifty (50) antioxidants using pharmacokinetic ADMET profiling, bioactivity assessment, physicochemical studies, molecular docking investigation, molecular dynamics and Quantum mechanical-based Density Functional Theory (DFT) studies using Keap1 as the apoprotein control. Out of these 50 antioxidants, Maslinic acid (MASA), 18-alpha-glycyrrhetinic acid (18-AGA) and resveratrol stand out by passing the RO5 (Lipinski rule of 5) for the physicochemical properties and ADMET studies. These three compounds also show high binding affinity of -10.6 kJ/mol, -10.4 kJ/mol and -7.8 kJ/mol at the kelch pocket of Keap1 respectively. Analysis of the 20ns trajectories using RMSD, RMSF, ROG and h-bond parameters revealed the stability of these compounds after comparing them with Keap1 apoprotein. Furthermore, the electron donating and accepting potentials of these compounds was used to investigate their reactivity using Density Functional Theory (HOMO and LUMO) and it was revealed that resveratrol had the highest stability based on its low energy gap. Our results predict that the three compounds are potential drug candidates with domiciled therapeutic functions against oxidative stress-mediated diseases. However, resveratrol stands out as the compound with the best stability and therefore, could be the best candidate with the best therapeutic efficacy.

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Section: Resultsmentioning

confidence: 99%

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

Adelusi

Abdul-Hammed

Idris

et al. 2021

Heliyon

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“…Electrostatics potential plays an important role in molecular biology since it contributes to protein folding and stability, protein-protein interactions, ion binding, dimerization, protein-DNA/RNA interactions, and protein-microtubule binding (Shashikala et al, 2019). In particular, it is well-known that molecular electrostatics can be predictive of a molecule's chemical reactivity and its ability to form certain types of interactions (Rathi et al, 2020). Differences in the topology and surface electrostatic potential surrounding the cleft are thought to determine the specificity of TLPs to their target proteins and ligands (Min et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterisation of Soybean Osmotins and Their Involvement in Drought Stress Response

et al. 2021

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Osmotins are multifunctional proteins belonging to the thaumatin-like family related to plant stress responses. To better understand the functions of soybean osmotins in drought stress response, the current study presents the characterisation of four previously described proteins and a novel putative soybean osmotin (GmOLPa-like). Gene and protein structure as well as gene expression analyses were conducted on different tissues and developmental stages of two soybean cultivars with varying dehydration sensitivities (BR16 and EMB48 are highly and slightly sensitive, respectively). The analysed osmotin sequences share the conserved amino acid signature and 3D structure of the thaumatin-like family. Some differences were observed in the conserved regions of protein sequences and in the electrostatic surface potential. P21-like present the most similar electrostatic potential to osmotins previously characterised as promoters of drought tolerance in Nicotiana tabacum and Solanum nigrum. Gene expression analysis indicated that soybean osmotins were differentially expressed in different organs (leaves and roots), developmental stages (R1 and V3), and cultivars in response to dehydration. In addition, under dehydration conditions, the highest level of gene expression was detected for GmOLPa-like and P21-like osmotins in the leaves and roots, respectively, of the less drought sensitive cultivar. Altogether, the results suggest an involvement of these genes in drought stress tolerance.

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“…In contrast to atomic charges and electronegativity, which may be described as arbitrary and whose absolute values strongly depend on the context and applied method, it can be well approximated using modern quantum chemical techniques. New advances in machine learning may even establish it as a routine procedure in drug design (Rathi et al, 2020). To compare the electrostatic potential of our targets and map it to the HS and the experimental crystal structures, we computed the electron density map with the electrostatic potential using the Gaussian visualization software Gaussview 6.6.1 (Dennington et al, 2019) Schematic representation of the HOMO-LUMO gap and the orbital distribution of the HOMO and LUMO of the four compounds presented in this study as obtained at the B3LYP-D3BJ/6-311++G(d,p) level of theory.…”

Section: Figurementioning

confidence: 99%

Structural insight from intermolecular interactions and energy framework analyses of 2-substituted 6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-ones

Tojiboev¹,

Элмурадов²,

Mouhib³

et al. 2021

Acta Crystallogr Sect B

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The crystal structures of three mackinazolinone derivatives (2-amino-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-one at room temperature, and 2-nitro-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-one and N-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-2-yl)benzamide at 100 K) are explored using X-ray crystallography. To delineate the different intermolecular interactions and the respective interaction energies in the crystal architectures, energy framework analyses were carried out using the CE-B3LYP/6-31G(d,p) method implemented in the CrystalExplorer software. In the structures the different molecules are linked by C—H...O, C—H...N and N—H...O hydrogen bonds. Together with these hydrogen bonds, C—H...π and C—O...π interactions are involved in the formation of a three-dimensional crystal network. A Hirshfeld surface analysis allows the visualization of the two-dimensional fingerprint plots and the quantification of the contributions of H...H, H...C/C...H and H...O/O...H contacts throughout the different crystal structures. To obtain additional information on the intrinsic properties of our targets and to compare the experimental crystal structures with their respective conformations in the gas phase, quantum chemical calculations at the B3LYP-D3BJ/6-311++G(d,p) level of theory, including Grimme's D3 correction term and BJ damping functions, were carried out to account for intramolecular dispersion interactions. The identified energy gaps between the highest occupied and the lowest unoccupied molecular orbitals (HOMO–LUMO gap) of our targets in the gas phase and in two implicit solvents (methanol and dimethyl sulfoxide) allow us to quantify the impact of different substituents on the reactivity of mackinazolinone derivatives.

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Practical High-Quality Electrostatic Potential Surfaces for Drug Discovery Using a Graph-Convolutional Deep Neural Network

Cited by 100 publications

References 37 publications

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

Molecular Characterisation of Soybean Osmotins and Their Involvement in Drought Stress Response

Structural insight from intermolecular interactions and energy framework analyses of 2-substituted 6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-ones

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