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1.
J Biomol Struct Dyn ; : 1-11, 2023 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-37735921

RESUMO

Modern cancer therapy now routinely employs the blocking of many oncoproteins or pathways. With two or more medicines, multiple inhibitions are often accomplished via DML techniques. In this study, we developed 30 quinazolinone derivatives as PARP1 and STAT3 dual inhibitors using DML methods and these compounds were tested for their dual inhibitory effect on PARP1 and STAT3 using docking, MM-GBSA, and molecular dynamics simulation investigations. The docking studies of ligands against PARP1 and STAT3 were performed using the Glide module, in silico ADMET screening was performed using the quickprob module, binding energy calculation was performed using the Prime MM-GBSA module, MD simulation was performed using the Desmond module, and atomic charges were calculated using the Jaguar module of Schrodinger suite 2019-4. Of the substances studied, the derivative 1f has a considerable gliding score. The in silico ADMET characteristics are within the approved range. PRIME MM-GB/SA was used to compute the binding free energy, and the results are substantial. To investigate the dynamic behavior of the protein-ligand complex, compound 1f was subjected to MD simulation at 100 ns. The tested chemical 1f produced the greatest results in MD simulations and MM-GBSA calculations, indicating that this ligand can inhibit more effectively.Communicated by Ramaswamy H. Sarma.

2.
Curr Drug Res Rev ; 12(1): 16-25, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31755398

RESUMO

Oral drug delivery is the most widely utilized route of administration among all the routes that have been explored for systemic delivery of drugs via pharmaceutical products of different dosage form and this oral route provides maximum active surface area among all drug delivery system for administration of various drugs. The attractiveness of these dosage forms is due to awareness of toxicity and ineffectiveness of drugs when administered by oral conventional method in the form of tablets and capsules. Usually, conventional dosage form produces wide range of fluctuation in drug concentration in the bloodstream and tissues with consequent undesirable toxicity and poor efficiency. The maintenance of concentration of drug in plasma within therapeutic index is very critical for effective treatment. These factors as well as factors such as repetitive dosing and unpredictable absorption lead to the concept of oral modified drug delivery systems like Sustained release, prolonged release, modified release, extended release. These formulations are used to identify drug delivery systems that are designed to achieve or extend therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose. This review describes the basic information regarding modified release dosage form like designed to release their medication in controlled manner, criteria for selecting modified release dosage form and factors influencing the dosage and release pattern.


Assuntos
Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos , Preparações Farmacêuticas/administração & dosagem , Administração Oral , Cápsulas , Preparações de Ação Retardada , Desenho de Fármacos , Liberação Controlada de Fármacos , Humanos , Preparações Farmacêuticas/química , Comprimidos
3.
Curr Drug Res Rev ; 12(1): 63-71, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31823710

RESUMO

OBJECTIVE: A basic, powerful and isocratic chiral fluid chromatographic technique was created and approved for the enantiomeric partition of meclizine hydrochloride in pharmaceutical dose structure. METHODS: The chromatographic partition was accomplished on Phenomenex® Lux Cellulose 1 (250 mm x 4.6 mm i.d, 5 µm molecule size) section utilizing portable stage framework containing acetonitrile: 25mM ammonium bicarbonate (75:25%v /v). The versatile stage was siphoned on the segment at the stream pace of 1.0 mL/min, and UV recognition was done at 230 nm. RESULT: The breaking points of recognition and measurement were observed to be 0.25 µg/mL and 1.00 µg/mL individually, for 20µL infusion volume. The alignment bend demonstrated phenomenal linearity over the focus scope of 1-5 µg/mL for (±) meclizine enantiomers with a relationship coefficient (r2 = 0.999). The recuperation investigation of meclizine from tablet plan was observed to be 97.33% and 98.81% separately. Meclizine standard arrangement and versatile stage were observed to be steady for in any event 32h. The meclizine enantiomers were very much settled with mean maintenance times of about (+) Meclizine at 13.14 min and (-) Meclizine at 14.33 min individually. CONCLUSION: The created technique was broadly approved and demonstrated to be hearty, exact, exact and appropriate for the examination of meclizine enantiomers in tablet measurement structure and security investigations of meclizine.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Antagonistas dos Receptores Histamínicos H1/análise , Meclizina/análise , Química Farmacêutica , Antagonistas dos Receptores Histamínicos H1/química , Meclizina/química , Estereoisomerismo , Comprimidos , Fatores de Tempo
4.
Curr Drug Res Rev ; 11(2): 118-128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31513003

RESUMO

BACKGROUND: Human Epidermal development factor Receptor-2 (HER2) is a membrane tyrosine kinase which is overexpressed and gene amplified in human breast cancers. HER2 amplification and overexpression have been linked to important tumor cell proliferation and survival pathways for 20% of instances of breast cancer. 9-aminoacridines are significant DNA-intercalating agents because of their antiproliferative properties. OBJECTIVE: Some novel isoxazole substituted 9-anilinoacridines(1a-z) were designed by in-silico technique for their HER2 inhibitory activity. Docking investigations of compounds 1a-z are performed against HER2 (PDB id-3PP0) by using Schrodinger suit 2016-2. METHODS: Molecular docking study for the designed molecules 1a-z are performed by Glide module, in-silico ADMET screening by QikProp module and binding free energy by Prime-MMGBSA module of Schrodinger suit. The binding affinity of designed molecules 1a-z towards HER2 was chosen based on GLIDE score. RESULTS: Many compounds showed good hydrophobic communications and hydrogen bonding associations to hinder HER2. The compounds 1a-z, aside from 1z have significant Glide scores in the scope of - 4.91 to - 10.59 when compared with the standard Ethacridine (- 4.23) and Tamoxifen (- 3.78). The in-silico ADMET properties are inside the suggested about drug likeness. MM-GBSA binding of the most intense inhibitor is positive. CONCLUSION: The outcomes reveal that this study provides evidence for the consideration of isoxazole substituted 9-aminoacridine derivatives as potential HER2 inhibitors. The compounds, 1s,x,v,a,j,r with significant Glide scores may produce significant anti breast cancer activity and further in vitro and in vivo investigations may prove their therapeutic potential.


Assuntos
Amsacrina/análogos & derivados , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Isoxazóis/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Amsacrina/química , Amsacrina/farmacocinética , Amsacrina/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Simulação por Computador , Desenho de Fármacos , Etacridina/farmacologia , Feminino , Humanos , Ligação de Hidrogênio , Isoxazóis/química , Isoxazóis/farmacocinética , Modelos Moleculares , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Tamoxifeno/farmacologia
5.
Pak J Pharm Sci ; 24(2): 109-12, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21454157

RESUMO

The basic nucleus 4-(amino)-5-phenyl-l-4H-1,2,4-triazole-3-thiol was prepared by cyclisation of potassium dithiocarbazinate with hydrazine hydrate using water as solvent under reflux condition for 3-4 h. The compound which has been synthesized successfully was subjected to addition reaction with different aldehydes to synthesize Schiff bases. The compounds were confirmed by physical parameters (solubility, melting point), chromatographic methods (TLC) and at last spectroscopic methods (IR, NMR, and Mass). In order to ascertain the pharmaceutical application, the selective pharmacological screening of the derivatives was carried out according to the standard procedures. The compounds were screened for their antianxietic activity by elevated plus maze method, antidepressant activity by forced swim test. Among the synthesized compounds, the Schiff bases of benzaldehyde (5e), furfuraldehyde (5d) and 2,4-dichloro benzaldehyde (5a) showed extremely significant activities. Results indicate that these compounds may be potential candidates for managing CNS disorders. However further studies are required to substantiate the same which are underway in our lab.


Assuntos
Ansiolíticos/síntese química , Antidepressivos/síntese química , Triazóis/síntese química , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Antidepressivos/química , Antidepressivos/farmacologia , Masculino , Camundongos , Estrutura Molecular , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Triazóis/química , Triazóis/farmacologia
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