Discovery of newer pyrazole derivatives with potential anti-tubercular activity via 3D-QSAR based pharmacophore modelling, virtual screening, molecular docking and molecular dynamics simulation studies

Modi, Palmi; Patel, Shivani; Chhabria, Mahesh T.

doi:10.1007/s11030-022-10511-8

Cited by 7 publications

(3 citation statements)

References 46 publications

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“…Where ΔE gas is gas‐phase interaction energy, ΔE ele is electrostatic energies, ΔE int is internal energies, ΔE vdw is vander Waal interaction energies, ΔG solv is solvation energy, ΔG GB is electrostatic solvation energy, and ΔG SA is surface area energy difference between protein‐ligand complex and protein and ligand [69] …”

Section: Methodsmentioning

confidence: 99%

Discovery of Thiadiazoles as Human Dihydroorotate Dehydrogenase (hDHODH) Inhibitors by Combined Structure‐Based Modelling Methods

Gehlot,

Kumar,

Kumar

et al. 2024

ChemistrySelect

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This study involves the design of novel thiadiazole derivatives as hDHODH inhibitors using various structure‐based approaches such as pharmacophore modelling, high‐throughput virtual screening (HTVS), prediction of ADMET parameters, docking and molecular dynamics (MD) studies. We used the validated co‐crystal structure of hDHODH to create the six‐feature pharmacophore model ADHRRR, which was validated by the Güner‐Henry scoring (GH score=0.81) approach, enrichment calculations (enrichment factor=51), area under the curve (0.93), receiving operating characteristic (ROC) curve (0.89), and ROC′s Boltzmann‐enhanced discrimination, known as BEDROC (α=8) (0.859), (α=20) (0.828), (α=160) (0.912). Pharmacophore model as a 3D search query was used for the screening of zinc database followed by docking investigations and energy calculation (Prime/MMGBSA). For the design of novel compounds, we selected the thiadiazole moiety as the central scaffold and various functional groups based on pharmacophoric characters and binding interactions. In docking study, designed compounds showed favourable interactions with Gln47 and Arg136 at the active site of the hDHODH enzyme, and optimal drug likeness properties for ADMET prediction study. Stability of enzyme‐ligand complex was validated by MD simulation study with RMSD, RMSF and RoG calculations. These findings suggested that novel thiadiazoles are potential candidates as hDHODH inhibitors and anticancer agents.

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Section: Methodsmentioning

confidence: 99%

Discovery of Thiadiazoles as Human Dihydroorotate Dehydrogenase (hDHODH) Inhibitors by Combined Structure‐Based Modelling Methods

Gehlot,

Kumar,

Kumar

et al. 2024

ChemistrySelect

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“…The preliminary SAR considerations suggested that the presence of the electron-withdrawing substituents at both R and R positions is beneficial for antibacterial activity, while electron-donating groups caused a remarkable reduction in potency. In addition, molecular docking studies suggested InhA, an enzyme involved in fatty acid synthesis and target for the development of novel antitubercular agents, as a possible target for the most potent derivatives [83].…”

Section: Antimalarial 5apsmentioning

confidence: 99%

Amino-Pyrazoles in Medicinal Chemistry: A Review

Lusardi

Spallarossa

Brullo

2023

IJMS

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A pyrazole nucleus is an easy-to-prepare scaffold with large therapeutic potential. Consequently, the search for new pyrazole-based compounds is of great interest to the academic community as well as industry. In the last ten years, a large number of papers and reviews on the design, synthesis, and biological evaluation of different classes of pyrazoles and many pyrazole-containing compounds have been published. However, an overview of pyrazole derivatives bearing a free amino group at the 3, 4, or 5 position (namely, 3-aminopyrazoles, 4-aminopyrazoles, and 5-aminopyrazoles, respectively) and their biological properties is still missing, despite the fact that aminopyrazoles are advantageous frameworks able to provide useful ligands for receptors or enzymes, such as p38MAPK, and different kinases, COX and others, as well as targets important for bacterial and virus infections. With the aim to fill this gap, the present review focuses on aminopyrazole-based compounds studied as active agents in different therapeutic areas, with particular attention on the design and structure-activity relationships defined by each class of compounds. In particular, the most relevant results have been obtained for anticancer/anti-inflammatory compounds, as the recent approval of Pirtobrutinib demonstrates. The data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using “aminopyrazole” as the keyword.

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“…In the drug designing process, molecular docking can be used as a tool to identify the structural requirement for efficient protein-ligand binding, virtual screening, drug repositioning, identification of the compounds that can target more than one protein of the same disease and prediction of drug off-target activity, and many more (Pinzi and Rastelli, 2019). Ample studies are reported that have implemented the use of molecular docking and/or hybrid with experimental studies to search for various anticancer (Lone et al, 2017;Tutone and Almerico, 2017;Bhattacharya et al, 2022;El-Sayed et al, 2022a, 2022cGhosh et al, 2022;Khanam et al, 2022;Obakachi et al, 2022), antimalarial (Manhas et al, 2016(Manhas et al, , 2018(Manhas et al, , 2019a(Manhas et al, , 2019bBenjamin et al, 2022), antitubercular (Lone et al, 2018;Akki et al, 2022;Kaur and Singh, 2022;Modi et al, 2022;Sanka et al, 2022), etc., molecules. This depicts the importance of docking in the field of rational drug design.…”

Section: Introductionmentioning

confidence: 99%

A comprehensive analysis of the role of molecular docking in the development of anticancer agents against the cell cycle CDK enzyme

SOLANKI¹,

RANA²,

Jha³

et al. 2023

Biocell

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Cancer is considered one of the most lethal diseases responsible for causing deaths worldwide. Although there have been many breakthroughs in anticancer development, cancer remains the major cause of death globally. In this regard, targeting cancer-causing enzymes is one of the efficient therapeutic strategies. Biological functions like cell cycle, transcription, metabolism, apoptosis, and other depend primarily on cyclin-dependent kinases (CDKs). These enzymes help in the replication of DNA in the normal cell cycle process, and deregulation in the functioning of any CDK can cause abnormal cell growth, which leads to cancer. This review is focused on anticancer drug discovery against cell cycle CDK enzyme using an in silico technique, i.e., molecular docking studies. Molecular docking helps in deciphering the key interactions formed within the inhibitor and the respective enzyme. This concise study provides an overview of the most current in silico research advancements made in the field of anticancer drug discovery. The findings presented in the current review article can help in understanding the nature of inhibitor-target interactions and provide information on the structural and molecular prerequisites for the inhibition of cell cycle CDKs.

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Discovery of newer pyrazole derivatives with potential anti-tubercular activity via 3D-QSAR based pharmacophore modelling, virtual screening, molecular docking and molecular dynamics simulation studies

Cited by 7 publications

References 46 publications

Discovery of Thiadiazoles as Human Dihydroorotate Dehydrogenase (hDHODH) Inhibitors by Combined Structure‐Based Modelling Methods

Discovery of Thiadiazoles as Human Dihydroorotate Dehydrogenase (hDHODH) Inhibitors by Combined Structure‐Based Modelling Methods

Amino-Pyrazoles in Medicinal Chemistry: A Review

A comprehensive analysis of the role of molecular docking in the development of anticancer agents against the cell cycle CDK enzyme

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