Identification of potent aldose reductase inhibitors as antidiabetic (Anti-hyperglycemic) agents using QSAR based virtual Screening, molecular Docking, MD simulation and MMGBSA approaches

Bakal, Ravindra L.; Jawarkar, Rahul D.; Manwar, Jagdish V.; Jaiswal, Minal S.; Ghosh, Arabinda; Gandhi, Ajaykumar; Zaki, Magdi E. A.; Al‐Hussain, Sami A.; Samad, Abdul; Masand, Vijay H.; Mukerjee, Nobendu; Bukhari, Syed Nasir Abbas; Sharma, Praveenkumar; Lewaa, Israa

doi:10.1016/j.jsps.2022.04.003

Cited by 19 publications

(5 citation statements)

References 39 publications

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“…In the Material Studio software interface, multi-variant equations (models) have been generated by blending both the genetic function algorithm technique (GFA) and the multi-linear regression technique (MLR) [ [32] , [33] , [34] ]. The built models using the training set were further tested by the confirmation sets to determine their predictive strength [ 35 ].…”

Section: Methodsmentioning

confidence: 99%

Chemo-informatics applications in the design of novel 7-keto-sempervirol derivatives as SmCB1 inhibitors with potential for treatment of Schistosomiasis

Anyubaga,

Shallangwa,

Uzairu

et al. 2024

Heliyon

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Section: Methodsmentioning

confidence: 99%

Chemo-informatics applications in the design of novel 7-keto-sempervirol derivatives as SmCB1 inhibitors with potential for treatment of Schistosomiasis

Anyubaga,

Shallangwa,

Uzairu

et al. 2024

Heliyon

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“…A database of 1615 FDA molecules was obtained from the Zinc database for QSAR-based VS. Before calculating molecular descriptors, 3D-structures of molecules were generated in the same way that the modelling set was. Based on the estimated chemical descriptors, a well-validated six-parametric division set QSAR model was used to predict the arginase-I inhibitory activity of 1615 FDA molecules obtained from the zinc database ( Jawarkar et al, 2022a ; Bakal et al, 2022 ; Jawarkar et al, 2022b ; Ghosh et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

In-silico studies to recognize repurposing therapeutics toward arginase-I inhibitors as a potential onco-immunomodulators

et al. 2023

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Rudolf Virchow was the first person to point out the important link between immune function and cancer. He did this by noticing that leukocytes were often found in tumors. Overexpression of arginase 1 (ARG1) and inducible nitric oxide synthase (iNOS) in myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs) depletes both intracellular and extracellular arginine. TCR signalling is slowed as a result, and the same types of cells produce reactive oxygen and nitrogen species (ROS and RNS), which aggravates the situation. Human arginase I is a double-stranded manganese metalloenzyme that helps L-arginine break down into L-ornithine and urea. Thus, a quantitative structure-activity relationship (QSAR) analysis was performed to unearth the unrecognised structural aspects crucial for arginase-I inhibition. In this work, a balanced QSAR model with good prediction performance and clear mechanistic interpretation was developed using a dataset of 149 molecules encompassing a broad range of structural scaffolds and compositions. The model was made to meet OECD standards, and all of its validation parameters have values that are higher than the minimum requirements (R2tr = 0.89, Q2LMO = 0.86, and R2ex = 0.85). The present QSAR study linked structural factors to arginase-I inhibitory action, including the proximity of lipophilic atoms to the molecule’s centre of mass (within 3A), the position of the donor to the ring nitrogen (exactly 3 bonds away), and the surface area ratio. As OAT-1746 and two others are the only arginase-I inhibitors in development at the time, we have performed a QSAR-based virtual screening with 1650 FDA compounds taken from the zinc database. In this screening, 112 potential hit compounds were found to have a PIC50 value of less than 10 nm against the arginase-I receptor. The created QSAR model’s application domain was evaluated in relation to the most active hit molecules identified using QSAR-based virtual screening, utilising a training set of 149 compounds and a prediction set of 112 hit molecules. As shown in the Williams plot, the top hit molecule, ZINC000252286875, has a low leverage value of HAT i/i h* = 0.140, placing it towards the boundary of the usable range. Furthermore, one of 112 hit molecules with a docking score of −10.891 kcal/mol (PIC50 = 10.023 M) was isolated from a study of arginase-I using molecular docking. Protonated ZINC000252286875-linked arginase-1 showed 2.9 RMSD, whereas non-protonated had 1.8. RMSD plots illustrate protein stability in protonated and non-protonated ZINC000252286875-bound states. Protonated-ZINC000252286875-bound proteins contain 25 Rg. The non-protonated protein-ligand combination exhibits a 25.2-Rg, indicating compactness. Protonated and non-protonated ZINC000252286875 stabilised protein targets in binding cavities posthumously. Significant root mean square fluctuations (RMSF) were seen in the arginase-1 protein at a small number of residues for a time function of 500 ns in both the protonated and unprotonated states. Protonated and non-protonated ligands interacted with proteins throughout the simulation. ZINC000252286875 bound Lys64, Asp124, Ala171, Arg222, Asp232, and Gly250. Aspartic acid residue 232 exhibited 200% ionic contact. 500-ns simulations-maintained ions. Salt bridges for ZINC000252286875 aided docking. ZINC000252286875 created six ionic bonds with Lys68, Asp117, His126, Ala171, Lys224, and Asp232 residues. Asp117, His126, and Lys224 showed 200% ionic interactions. In protonated and deprotonated states, GbindvdW, GbindLipo, and GbindCoulomb energies played crucial role. Moreover, ZINC000252286875 meets all of the ADMET standards to serve as a drug. As a result, the current analyses were successful in locating a novel and potent hit molecule that inhibits arginase-I effectively at nanomolar concentrations. The results of this investigation can be used to develop brand-new arginase I inhibitors as an alternative immune-modulating cancer therapy.

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“…Before calculating molecular descriptors, 3D structures of molecules were built in the same manner as the PLOS ONE modeling set. The chemical descriptors were then calculated, and a well-validated six-parametric divided set QSAR model was used to predict Ant-SAR activity in novel compounds [71][72][73][74].…”

Section: Qsar Based Virtual Screeningmentioning

confidence: 99%

Application of in-silico drug discovery techniques to discover a novel hit for target-specific inhibition of SARS-CoV-2 Mpro’s revealed allosteric binding with MAO-B receptor: A theoretical study to find a cure for post-covid neurological disorder

Zaki,

AL-Hussain,

Al-Mutairi

et al. 2024

PLoS ONE

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Several studies have revealed that SARS-CoV-2 damages brain function and produces significant neurological disability. The SARS-CoV-2 coronavirus, which causes COVID-19, may infect the heart, kidneys, and brain. Recent research suggests that monoamine oxidase B (MAO-B) may be involved in metabolomics variations in delirium-prone individuals and severe SARS-CoV-2 infection. In light of this situation, we have employed a variety of computational to develop suitable QSAR model using PyDescriptor and genetic algorithm-multilinear regression (GA-MLR) models (R2 = 0.800–793, Q2LOO = 0.734–0.727, and so on) on the data set of 106 molecules whose anti-SARS-CoV-2 activity was empirically determined. QSAR models generated follow OECD standards and are predictive. QSAR model descriptors were also observed in x-ray-resolved structures. After developing a QSAR model, we did a QSAR-based virtual screening on an in-house database of 200 compounds and found a potential hit molecule. The new hit’s docking score (-8.208 kcal/mol) and PIC50 (7.85 M) demonstrated a significant affinity for SARS-CoV-2’s main protease. Based on post-covid neurodegenerative episodes in Alzheimer’s and Parkinson’s-like disorders and MAO-B’s role in neurodegeneration, the initially disclosed hit for the SARS-CoV-2 main protease was repurposed against the MAO-B receptor using receptor-based molecular docking, which yielded a docking score of -12.0 kcal/mol. This shows that the compound that inhibits SARS-CoV-2’s primary protease may bind allosterically to the MAO-B receptor. We then did molecular dynamic simulations and MMGBSA tests to confirm molecular docking analyses and quantify binding free energy. The drug-receptor complex was stable during the 150-ns MD simulation. The first computational effort to show in-silico inhibition of SARS-CoV-2 Mpro and allosteric interaction of novel inhibitors with MAO-B in post-covid neurodegenerative symptoms and other disorders. The current study seeks a novel compound that inhibits SAR’s COV-2 Mpro and perhaps binds MAO-B allosterically. Thus, this study will enable scientists design a new SARS-CoV-2 Mpro that inhibits the MAO-B receptor to treat post-covid neurological illness.

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Identification of potent aldose reductase inhibitors as antidiabetic (Anti-hyperglycemic) agents using QSAR based virtual Screening, molecular Docking, MD simulation and MMGBSA approaches

Cited by 19 publications

References 39 publications

Chemo-informatics applications in the design of novel 7-keto-sempervirol derivatives as SmCB1 inhibitors with potential for treatment of Schistosomiasis

Chemo-informatics applications in the design of novel 7-keto-sempervirol derivatives as SmCB1 inhibitors with potential for treatment of Schistosomiasis

In-silico studies to recognize repurposing therapeutics toward arginase-I inhibitors as a potential onco-immunomodulators

Application of in-silico drug discovery techniques to discover a novel hit for target-specific inhibition of SARS-CoV-2 Mpro’s revealed allosteric binding with MAO-B receptor: A theoretical study to find a cure for post-covid neurological disorder

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