Fast, Efficient Fragment-Based Coordinate Generation for Open Babel

Yoshikawa, N.; Hutchison, Geoffrey

doi:10.26434/chemrxiv.7791947.v2

Cited by 5 publications

(5 citation statements)

References 43 publications

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“…54 Following a visual examination of each 3D compound, the structures were initially downloaded in SDF (structure data format) and translated to PDB format using Open Babel software. 55 All the 3D compounds were subjected to Pfizer's rule of five for evaluating drug-likeness criteria. 56 Following the evaluation, only 3D bioactive flavonoids which satisfied all five of Pfizer's rule of five physicochemical requirements were chosen because any one infraction was treated as a failure or an elimination aspect.…”

Section: Metalr: This Logistic Regression-based Methods Calledmentioning

confidence: 99%

Transcript-Level In Silico Analysis of Alzheimer’s Disease-Related Gene Biomarkers and Their Evaluation with Bioactive Flavonoids to Explore Therapeutic Interactions

Azmi,

Ahmed,

Ahmed

et al. 2023

ACS Omega

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Alzheimer's disease (AD) is a progressive brain disorder that can significantly affect the quality of life. We used a variety of in silico tools to investigate the transcript-level mutational impact of exonic missense rare variations (single nucleotide polymorphisms, SNPs) on protein function and to identify potential druggable protein cavities that correspond to potential therapeutic targets for the management of AD. According to the NIA-AA (National Institute on Aging-Alzheimer's Association) framework, we selected three AD biomarker genes (APP, NEFL, and MAPT). We systematically screened transcript-level exonic rare SNPs from these genes with a minor allele frequency of 1% in 1KGD (1000 Genomes Project Database) and gnomAD (Genome Aggregation Database). With downstream functional effect predictions, a single variation (rs182024939: K > N) of the MAPT gene with nine transcript SNPs was identified as the most pathogenic variation from the large dataset of mutations. The machine learning consensus classifier predictor categorized these transcript-level SNPs as the most deleterious variations, resulting in a large decrease in protein structural stability (ΔΔG kcal/mol). The bioactive flavonoid library was screened for drug-likeness and toxicity risk. Virtual screening of eligible flavonoids was performed using the MAPT protein. Identification of druggable protein-binding cavities showed VAL305, GLU655, and LYS657 as consensus-interacting residues present in the MAPT-docked top-ranked flavonoid compounds. The MM/PB(GB)SA analysis indicated hesperetin (−5.64 kcal/ mol), eriodictyol (−5.63 kcal/mol), and sakuranetin (−5.60 kcal/mol) as the best docked flavonoids with the near-native binding pose. The findings of this study provide important insights into the potential of hesperetin as a promising flavonoid that can be utilized for further rational drug design and lead optimization to open new gateways in the field of AD therapeutics.

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Section: Metalr: This Logistic Regression-based Methods Calledmentioning

confidence: 99%

Transcript-Level In Silico Analysis of Alzheimer’s Disease-Related Gene Biomarkers and Their Evaluation with Bioactive Flavonoids to Explore Therapeutic Interactions

Azmi,

Ahmed,

Ahmed

et al. 2023

ACS Omega

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“…3 For all sources, the largest substructure was retained (i.e., removing solvent or salts from the crystallographic unit cells). For compounds without initial 3D coordinates, Open Babel 3.1 [31][32][33] was used to generate initial coordinates. As noted above, the total set of compounds included over 3 million unique molecules.…”

Section: Methodsmentioning

confidence: 99%

Systematic Comparison of Experimental Crystallographic Geometries and Gas-Phase Computed Conformers for Torsion Preferences

Folmsbee

Koes

Hutchison

2022

Preprint

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We have performed exhaustive torsion sampling on more than 3 million compounds using the GFN2 method and performed a comparison of experimental crystallographic and gas-phase conformers. Many conformer sampling methods derive torsional angle distributions from experimental crystallographic data, limiting the torsion preferences to molecules that must be stable, synthetically accessible, and able to be crystallized. In this work, we evaluate the differences in torsional preferences of experimental crystallographic geometries and gas-phase computed conformers from a broad selection of compounds to determine whether torsional angle distributions obtained from semi-empirical methods are suitable for conformer sampling. We find that differences in torsion preferences can be mostly attributed to a lack of available experimental crystallographic data, with some deviations derived from gas-phase geometry differences. GFN2 demonstrates the ability to provide accurate and reliable torsional preferences that can provide a basis for new methods free from limitations of experimental data collection. We provide Gaussian-based fits and sampling distributions suitable for torsion sampling, and propose an alternative to ETKDG using quantum-torsion derived distance geometry methods (QTDG).

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“…To simulate binding affinity between protein and ligands, two docking tools, AutoDock Vina (version 1.1.2) 17 and RosettaCommons (version 3.11) 18-20 were used. Since AutoDock Vina only takes Protein Data Bank, Partial Charge (Q), & Atom Type (T) (PDBQT) formats as input, we used OpenBabel (version 3.0.0) 21 to convert SDF to PDBQT. The entire protein is taken as the search space.…”

Section: Methodsmentioning

confidence: 99%

Potential Therapeutic Agents for COVID-19 Based on the Analysis of Protease and RNA Polymerase Docking

Chang¹,

Tung²,

Lee³

et al. 2020

Preprint

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The outbreak of novel coronavirus (COVID-19) infections in 2019 is in dire need of finding potential therapeutic agents. In this study, we used molecular docking to repurpose HIV protease inhibitors and nucleoside analogues for COVID-19, with evaluations based on docking scores calculated by AutoDock Vina and RosettaCommons. Our results suggest that Indinavir and Remdesivir possess the best docking scores, and comparison of the docking sites of the two drugs reveal a near perfect dock in the overlapping region of the protein pockets. After further investigation of the functional regions inferred from the proteins of SARS coronavirus, we discovered that Indinavir does not dock on any active sites of the protease, which may give rise to concern in regards to the efficacy of Indinavir. On the other hand, the docking site of Remdesivir is not compatible with any known functional regions, including template binding motifs, polymerization motifs and nucleoside triphosphate (NTP) binding motifs. However, when we tested the active form (CHEMBL2016761) of Remdesivir, the docking site revealed a perfect dock in the overlapping region of the NTP binding motif. This result suggests that Remdesivir could be a potential therapeutic agent. Clinical trials still must be done in order to confirm the curative effect of these drugs.

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Fast, Efficient Fragment-Based Coordinate Generation for Open Babel

Cited by 5 publications

References 43 publications

Transcript-Level In Silico Analysis of Alzheimer’s Disease-Related Gene Biomarkers and Their Evaluation with Bioactive Flavonoids to Explore Therapeutic Interactions

Transcript-Level In Silico Analysis of Alzheimer’s Disease-Related Gene Biomarkers and Their Evaluation with Bioactive Flavonoids to Explore Therapeutic Interactions

Systematic Comparison of Experimental Crystallographic Geometries and Gas-Phase Computed Conformers for Torsion Preferences

Potential Therapeutic Agents for COVID-19 Based on the Analysis of Protease and RNA Polymerase Docking

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