Computational pharmacology and computational chemistry of 4-hydroxyisoleucine: Physicochemical, pharmacokinetic, and DFT-based approaches

Ahmad, Imad; Kuznetsov, Aleksey E.; Pirzada, Abdul Saboor; Alsharif, Khalaf F.; Daglia, Maria; Khan, Haroon

doi:10.3389/fchem.2023.1145974

Cited by 33 publications

(12 citation statements)

References 92 publications

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“…It has low GIT absorption without CNS side effects (cannot cross the BBB). There were no PAINS structural toxicity alerts [ 54 ]. The results assumed its ability to inhibit non-metabolizing enzymes (CYP2C9, CYP1A2, CYP2C19, CYP3A4, CYP2D6), indicating the hepatotoxicity’s non-existence, but it disclosed BRENK structural toxicity alerts due to the imine group existence.…”

Section: Resultsmentioning

confidence: 99%

Discovery of Pyrano[2,3-c]pyrazole Derivatives as Novel Potential Human Coronavirus Inhibitors: Design, Synthesis, In Silico, In Vitro, and ADME Studies

Allayeh,

El-boghdady,

Said

et al. 2024

Pharmaceuticals

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The SARS-CoV-2 pandemic at the end of 2019 had major worldwide health and economic consequences. Until effective vaccination approaches were created, the healthcare sectors endured a shortage of operative treatments that might prevent the infection’s spread. As a result, academia and the pharmaceutical industry prioritized the development of SARS-CoV2 antiviral medication. Pyranopyrazoles have been shown to play a prominent function in pharmaceutical chemistry and drug sighting because of their significant bioactive properties. We provide herein a novel sequence of pyranopyrazoles and their annulated systems whose antiviral efficacy and cytotoxicity were explored versus human coronavirus 229E (HCoV-229E) Vero-E6 cell lines as a model for the Coronaviridae family. Fifteen synthetic congeners pointed out miscellaneous antiviral efficacies against HCoV-229E with variable inhibition degrees. Compound 18 showed a high selectivity index (SI = 12.6) that established spectacular inhibitory capacity against human coronavirus 229E. Compounds 6, 7, and 14 exposed moderate efficacies. Compounds 6, 7, 14, and 18 exhibited substantial antiviral action through the replication phase with reduction percentages extending from 53.6%, 60.7%, and 55% to 82.2%, correspondingly. Likewise, when assessed to the positive control tipranavir (88.6%), the inhibitory efficiency of compounds 6, 7, 14, and 18 versus the SARS-CoV2 Mpro provided high percentages of 80.4%, 73.1%, 81.4% and up to 84.5%, respectively. In silico studies were performed to investigate further the biological activity and the target compounds’ physical and chemical features, including molecular dynamic (MD) simulations, protein–ligand docking, ADME studies, and density functional theory (DFT) calculations. These inquiries demonstrated that this series of metabolically stable pyranopyrazoles and their annulated systems are effective human coronavirus inhibitors that inhibit the viral Mpro protein and may have emerged as a novel COVID-19 curative option.

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Section: Resultsmentioning

confidence: 99%

Discovery of Pyrano[2,3-c]pyrazole Derivatives as Novel Potential Human Coronavirus Inhibitors: Design, Synthesis, In Silico, In Vitro, and ADME Studies

Allayeh,

El-boghdady,

Said

et al. 2024

Pharmaceuticals

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“…The computed volume of distribution (VD) was 0.478 L/kg. The range between 0.04 to 20 L/kg is ideal for VD ( 38 ). The score of 0.559 indicates that the flavan-4-ol has a greater probability of blood–brain barrier penetration.…”

Section: Resultsmentioning

confidence: 99%

Probing the potential of bioactive compounds of millets as an inhibitor for lifestyle diseases: molecular docking and simulation-based approach

Nagre,

Singh,

Ghoshal

et al. 2023

Front. Nutr.

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Millets are becoming more popular as a healthy substitute for people with lifestyle disorders. They offer dietary fiber, polyphenols, fatty acids, minerals, vitamins, protein, and antioxidants. The nutritional importance of millets leads to the present in-silico study of selective bioactive compounds docked against the targets of lifestyle diseases, viz., diabetes, hypertension, and atherosclerosis using molecular docking and molecular simulations approach. Pharmacokinetic analysis was also carried out to analyse ADME properties and toxicity analysis, drug-likeliness, and finally target prediction for new targets for uncharacterized compounds or secondary targets for recognized molecules by Swiss Target Prediction was also done. The docking results revealed that the bioactive compound flavan-4-ol, among all the 50 compounds studied, best docked to all the four targets of lifestyle diseases, viz., Human dipeptidyl peptidase IV (−5.94 kcal mol−1 binding energy), Sodium-glucose cotransporter-2 (−6.49 kcal mol−1) diabetes-related enzyme, the Human angiotensin-converting enzyme (−6.31 kcal mol−1) which plays a significant role in hypertension, and Proprotein convertase subtilisin kexin type 9 (−4.67 kcal mol−1) for atherosclerosis. Molecular dynamics simulation analysis substantiates that the flavan-4-ol forms a better stability complex with all the targets. ADMET profiles further strengthened the candidature of the flavan-4-ol bioactive compound to be considered for trial as an inhibitor of targets DPPIV, SGLT2, PCSK9, and hACE. We suggest that more research be conducted, taking Flavon-4-ol into account where it can be used as standard treatment for lifestyle diseases.

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“…Conversely, the LUMO, signifying the ability to accept electrons, usually resides near peptide bonds with electron-withdrawing groups. By introducing electron-donating groups in the HOMO orbital or electron-withdrawing groups in the LUMO orbital, it is possible to augment the energy gap, which may enhance the stability of antimicrobial peptides [ 71 , 72 , 73 , 74 ].…”

Section: Discussionmentioning

confidence: 99%

Rationally Designed Novel Antimicrobial Peptides Targeting Chitin Synthase for Combating Soybean Phytophthora Blight

Ran,

Shehzadi,

Liang

et al. 2024

IJMS

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Soybean phytophthora blight is a severe menace to global agriculture, causing annual losses surpassing USD 1 billion. Present crop loss mitigation strategies primarily rely on chemical pesticides and disease-resistant breeding, frequently surpassed by the pathogens’ quick adaptive evolution. In this urgent scenario, our research delves into innovative antimicrobial peptides characterized by low drug resistance and environmental friendliness. Inhibiting chitin synthase gene activity in Phytophthora sojae impairs vital functions such as growth and sporulation, presenting an effective method to reduce its pathogenic impact. In our study, we screened 16 previously tested peptides to evaluate their antimicrobial effects against Phytophthora using structure-guided drug design, which involves molecular docking, saturation mutagenesis, molecular dynamics, and toxicity prediction. The in silico analysis identified AMP_04 with potential inhibitory activity against Phytophthora sojae’s chitin synthase. Through three rounds of saturation mutagenesis, we pin-pointed the most effective triple mutant, TP (D10K, G11I, S14L). Molecular dynamic simulations revealed TP’s stability in the chitin synthase-TP complex and its transmembrane mechanism, employing an all-atom force field. Our findings demonstrate the efficacy of TP in occupying the substrate-binding pocket and translocation catalytic channel. Effective inhibition of the chitin synthase enzyme can be achieved. Specifically, the triple mutant demonstrates enhanced antimicrobial potency and decreased toxicity relative to the wild-type AMP_04, utilizing a mechanism akin to the barrel-stave model during membrane translocation. Collectively, our study provides a new strategy that could be used as a potent antimicrobial agent in combatting soybean blight, contributing to sustainable agricultural practices.

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Computational pharmacology and computational chemistry of 4-hydroxyisoleucine: Physicochemical, pharmacokinetic, and DFT-based approaches

Cited by 33 publications

References 92 publications

Discovery of Pyrano[2,3-c]pyrazole Derivatives as Novel Potential Human Coronavirus Inhibitors: Design, Synthesis, In Silico, In Vitro, and ADME Studies

Discovery of Pyrano[2,3-c]pyrazole Derivatives as Novel Potential Human Coronavirus Inhibitors: Design, Synthesis, In Silico, In Vitro, and ADME Studies

Probing the potential of bioactive compounds of millets as an inhibitor for lifestyle diseases: molecular docking and simulation-based approach

Rationally Designed Novel Antimicrobial Peptides Targeting Chitin Synthase for Combating Soybean Phytophthora Blight

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