Modulating the phosphorylation status of target proteins through bifunctional molecules

Drug Discovery Today, Год журнала: 2025, Номер unknown, С. 104307 - 104307

Опубликована: Фев. 1, 2025

Язык: Английский

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Exploring the Anticancer Potential of Furanpydone A: A Computational Study on its Inhibition of MTHFD2 Across Diverse Cancer Cell Lines

Cell Biochemistry and Biophysics, Год журнала: 2024, Номер unknown

Опубликована: Авг. 7, 2024

Язык: Английский

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In-silico approaches to unravel the efficacy of naturally occurring C–C and C–O–C type biflavonoids towards the inhibition of MDM2–p53 interactions

Discover Chemistry., Год журнала: 2025, Номер 2(1)

Опубликована: Апрель 24, 2025

Язык: Английский

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Homology modeling, binding site identification, molecular docking and molecular dynamics simulation study of emerging and promising drug target of Wnt signaling – Human Porcupine enzyme

Results in Chemistry, Год журнала: 2024, Номер 7, С. 101482 - 101482

Опубликована: Янв. 1, 2024

Wnt signaling is a critical pathway involved in cell proliferation, differentiation and cellular homeostasis. To address treatment need of diseases associated with the dysregulated like cancer, Alzheimer's disease, Osteoporosis, Myocardial infarction etc.; small molecules that target very first unique component pathway, Porcupine enzyme, have been proven to be effective. Till date, none inhibitor has reached market. design novel inhibitors, there was crystal structure but 2019, it not resolved deposited protein data bank. So, an aim predict its 3D structure, homology modeling study performed using two distinct platforms; I-TASSER Molsoft ICMPro so we could use best validated model for designing NCEs. Both generated models were compared through Ramachandran plot, Protein health tool ICM other tools available on metaserver, SAVES v6.0. found better 84.6 % residues most favored region only 0.3 disallowed plot comparison 75.9 1.7 respectively model. The further refined 50 ns under MD simulation where got stabilized after 36 ns. Quantification done by Radius Gyration (ROG) showed larger ROG value 23.25°A which indicated closely packed structure. Binding site predicted identified binding pocket identifier used molecular docking known inhibitors IWP-2, IWP-3, IWP-L6, LKG974. Key residues; Arg124, Phe257, Leu261, Val302, Trp305, Asn306, Ser310, Leu313, His341, Phen345, Ala349, Val350 etc. interaction can useful porcupine future.

Язык: Английский

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Targeting the Cyclin-Dependent Kinase Family in Anticancer Drug Discovery: From Computational to Experimental Studies

Chemical Physics Impact, Год журнала: 2024, Номер 9, С. 100768 - 100768

Опубликована: Ноя. 2, 2024

Язык: Английский

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Screening of synthesized perimidine compounds for the assessment of antimicrobial potential: in-vitro and in-silico molecular docking and molecular dynamics simulation studies

Discover Chemistry., Год журнала: 2024, Номер 1(1)

Опубликована: Окт. 9, 2024

Presently, antimicrobial resistance is a major and worldwide concern due to high rate of mutation in microorganisms, widespread use, lack efficacy drugs, low drug discovery rate. Considering the importance N-heterocycles as antibiotics, perimidine derivatives 3(a–v) have been synthesized via cyclocondensation reaction 1,8-diaminonaphthalene aryl aldehydes. Further, perimidines were screened potent agents in-vitro, in-silico, ADME MD simulation studies. All 22 studied against two-gram +ve (E. coli P. aeruginosa), −ve (S. aureus B. subtilis), two fungal (A. niger S. cerevisiae) strains using ciprofloxacin fluconazole reference drugs. The in-vitro study results showed that compounds 3e, 3h, 3l, 3m most 3(a–d), 3(g–i), 3s active subtilis compared standard. Furthermore, molecular docking studies performed Dihydrofolate reductase (PDB Id: 3SRW) from aureus, DNA gyrase 4DUH) E. coli, ERG11 gene 4LXJ). Compounds 3f, 3f/3m, 3o found bind efficiently with highest binding energy − 10.6, 9.6, 11.3kcal/mol depicting potential inhibitor 3SRW, 4DUH, 4LXJ receptor protein, respectively. drug-likeness properties SwissADME program. To further validate these findings, dynamics simulations conducted evaluate their stability. From studies, it was observed all shortlisted displayed stable within site selected proteins.

Язык: Английский

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Structure‐Based Computational Approach in Search of the Potent Molecules Targeting Phosphoglycerate Dehydrogenase (PHGDH) Enzyme for Cancer Treatment

ChemistrySelect, Год журнала: 2024, Номер 9(41)

Опубликована: Окт. 28, 2024

Abstract This work aims to target phosphoglycerate dehydrogenase (PHGDH), a promising druggable target, that is overexpressed in various types of cancer. A structure‐based approach was employed identify novel inhibitors against the enzyme. common five‐feature pharmacophore model (RRHDA) constructed using active site co‐crystalized ligands. These chemical features were responsible for showing inhibition. The generated models subsequently subjected validation method test set, receiver‐operator characteristic analysis, enrichment factor, and Güner–Henry studies. validated screening dataset natural compounds. screened unique compounds (1795) further selected interaction analysis study ligand binding affinity considering effect hydrogen bonding desolvation hydrophobic interactions contribution binding. which exhibited good efficiency pharmacokinetics pharmacodynamic study. finalized complexes simulation studies MM/PBSA‐based free energy calculations. expands possibilities development shortlisted molecules as anti‐cancer

Язык: Английский

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Vibrational, theoretical characterisation and In Silico investigation of Norcinnamolaurine: a natural lead for inhibiting AURKA and overcoming immune evasion in Triple-Negative Breast Cancer

Molecular Simulation, Год журнала: 2024, Номер 50(17-18), С. 1614 - 1630

Опубликована: Окт. 29, 2024

Alkaloids represent a diverse category of natural compounds with noteworthy pharmacological and therapeutic applications. Benzylisoquinoline alkaloids (BIAs) are distinguished by their varied structures potential medicinal properties. This study specifically investigates Norcinnamolaurine, BIA found in multiple species acknowledged for its advantages. In the current investigation, we comprehensively analyzed encompassing Frontier Molecular Orbital studies, vibrational spectroscopy, nonlinear optical properties, bond orbital evaluations, Fukui's analysis. Additionally, executed an E-pharmacophore-based screening utilizing AURKA-Norcinnamolaurine complex. The generated hypothesis underwent database screening; lead from Natural Product Drug Bank databases exhibited enhanced binding affinities ranging −8.602 to −7.148 kcal/mol, demonstrating improved interactions within AURKA pocket. Subsequently, identified were subjected further analysis via MMGBSA, DFT, Dynamics Simulations (MDS). Our findings indicate that Norcinnamolaurine exhibits superior affinity towards target protein. Significant outcomes also observed FMO studies. Moreover, MDS revealed resultant complexes maintained relative stability, exhibiting minimal deviation fluctuations. stability was corroborated through additional assessments using MMPBSA PCA/FEL methodologies.

Язык: Английский

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Development of Promising CDK5 Inhibitors Using Structure‐Based Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Approach

ChemistrySelect, Год журнала: 2024, Номер 9(43)

Опубликована: Ноя. 1, 2024

Abstract Cancer is highlighted as one of the deadliest diseases globally, with CDK5 identified a key enzyme in cancer progression. Despite its potential therapeutic target, developing inhibitors has been challenging. We used multicomplex‐based pharmacophore modeling on complexes, identifying hydrophobic groups, hydrogen bond donors, and acceptors crucial inhibition features. Validated models were for virtual screening drug‐like natural product databases. Thereafter, screened candidates selected to study their binding pattern efficiency enzyme. Four molecules shortlisted analyzed electrostatic (ESP) energy maps. Molecular dynamic simulations free calculations docked complexes revealed stable behavior all, three (CNP0299652, CNP0362830, CNP0009633) showing higher Poisson Boltzmann surface area continuum solvation (MM‐PBSA) scores than reference. These demonstrated characteristics, amino acid interactions, favorable electron potentials ESP plots, dynamicigher energy, highlighting inhibitors.

Язык: Английский

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Exploring the efficacy of some biologically active compounds as anti-hypertensive drugs: an insightful evaluation through DFT, molecular docking and molecular dynamics simulations

In Silico Pharmacology, Год журнала: 2024, Номер 13(1)

Опубликована: Дек. 24, 2024

Язык: Английский

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