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"Kanker serviks berada di peringkat ketiga sebagai kanker yang paling banyak menyebabkan kematian wanita di seluruh dunia dan menempati peringkat pertama di negara berkembang. Kanker ini disebabkan oleh infeksi human papilloma virus (HPV) yang memiliki onkoprotein E6 dan E7 yang mempengaruhi regulasi epigenetik termasuk overekspresi gen histone deacetylase (HDAC) yang menyebabkan karsinogenesis serviks. Sehingga HDAC menjadi target inhibisi yang potensial untuk terapi kanker serviks. Pada penelitian ini, suatu seri terbaru senyawa turunan 4-[(2-okso-1,3-thiazolidin-3-yl)karbonil]anilin dirancang sebagai inhibitor HDAC (HDACI) terbaru berdasarkan pendekatan de novo. Aktivitas inhibisi dari ligan rancangan ini terhadap HDAC kelas II Homo sapiens ditentukan melalui simulasi molecular docking. Analisis docking menghasilkan delapan ligan terbaik (F, Ib14, O38, Kb17, Gd40, Aa50, Gc42, dan Bb38) yang memiliki afinitas pengikatan lebih baik dibandingkan standar. Kemudian analisis interaksi mengindikasikan bahwa seluruh ligan terbaik membentuk koordinasi dengan kofaktor zinc pada charge-relay system HDAC, juga ikatan hidrogen dan interaksi hidrofobik yang penting pada aktivitas inhibisi dari inhibitor HDAC. Analisis QSAR (quantitative structure-activity relationship) dari senyawa ini, termasuk karakter farmakologi, bioaktivitas, mutagenisitas-karsinogenisitas, dan karakter ADMET (absorpsi, distribusi, metabolisme, ekskresi, dan toksisitas) dilakukan secara in silico. Melalui analisis ini, kedelapan ligan terbaik memenuhi Lipinski’s rule of five, memiliki drug score yang lebih baik dibanding standar, dan juga menunjukkan bioaktivitas, bioavailabilitas oral, dan karakter ADMET yang baik. Seluruh ligan terbaik juga mudah disintesis serta terbukti sebagai senyawa baru yang belum pernah disintesis sebelumnya. Kestabilan kompleks HDAC-ligan pada pengaruh pelarut dikalkulasi melalui simulasi molecular dynamics (MD). Berdasarkan simulasi ini, ligan terbaik yang membentuk kompleks dengan HDAC memiliki stabilitas yang baik berdasarkan RMSD (root mean square deviation) dan analisis interaksi. Ligan terbaik ini dapat disintesis untuk pengujian klinis lebih lanjut. Penelitian ini diharapkan dapat menghasilkan inhibitor HDAC yang lebih potensial sebagai obat terbaru untuk terapi kanker serviks.

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Cervical cancer ranks third as the most common deadly cancer in women worldwide and ranks first in developing countries. It is caused by human papillomavirus (HPV) infection which has E6 and E7 oncoproteins that induce epigenetic regulation including overexpression of histone deacetylases (HDACs) gene leading to cervical carcinogenesis. Thus HDACs becomes potential inhibition target for cervical cancer treatment.

In this study, a novel series of 4-[(2-oxo-1,3-thiazolidin-3-yl)carbonyl]aniline derivatives were designed as novel HDAC inhibitors (HDACIs) based on de novo approach. The inhibitory activity of these new designed ligands against Homo sapiens class II HDAC was determined by molecular docking simulation. Docking analysis has yielded eight best ligands (F, Ib14, O38, Kb17, Gd40, Aa50, Gc42, and Bb38) which have better binding affinity than the standards. Therefore, interaction analysis indicated that all best ligands were formed coordination with zinc cofactor in HDAC charge-relay system, also hydrogen bond and hydrophobic interaction which are essential for the HDAC inhibitory activities of these inhibitors.

QSAR (quantitative structure-activity relationship) analysis of these compounds including pharmacology properties, bioactivity, mutagenicity-carcinogenicity, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties were done in silico. Through this analysis, all eight best ligands meet Lipinski’s rule of five, have a better drug score than standards, and shows good bioactivity, oral bioavailability and ADMET properties. All best ligands also have a good synthetic accessibility and were proved to be new compounds that never been synthesized before. Stability of HDAC-ligand complexes in the presence of solvent were also calculated through molecular dynamics (MD) simulation.

Based on this simulation, all best ligands complex with corresponding HDAC have a good stability based on RMSD (root mean square deviation) and interaction analysis. The best ligands can be synthesized for further clinical testing. This study is expected to produce more potent HDAC inhibitors as novel drugs for cervical cancer treatment."

"This book was designed as a reference tool for pharmacists involved in the treatment of patients with infections. It is clinically oriented and designed to help students in all medical disciplines, and especially pharmacists and students of pharmacy who need information on choosing the correct drug, dose, and method of administration of an agent to patients with infectious diseases. "

"Quality by Design reflects the research and applied training conducted at Dartmouth Medical School under the leadership of Gene Nelson, Paul Batalden, and Marjorie Godfrey. The book includes the research results of high-performing clinical microsystems, illustrative case studies that highlight individual clinical programs, guiding principles that are easily applied, and tools, techniques, and methods that can be adapted by clinical practices and interdisciplinary clinical teams. The authors describe how to develop microsystems that can attain peak performance through active engagement of inter."

"The second most abundant transition element in living organisms, zinc spans all areas of metabolism, with zinc-containing proteins offering both established and potential drug targets. Drug design of zinc-enzyme inhibitors brings together functional and structural information relevant to these zinc-containing targets. With up-to-date overviews of the latest developments field, this unique and comprehensive text enables readers to understand zinc enzymes and evaluate them in a drug design context.With contributions from the leaders of today's research, Drug design of zinc-enzyme inhibitors covers such key topics as, major drug targets like carbonic anhydrases, matrix metalloproteinases, bacterial proteases, angiotensin-converting enzyme, histone deacetylase, and APOBEC3G, roles of recently discovered zinc-containing isozymes in cancer, obesity, epilepsy, pain management, malaria, and other conditions, cross reactivity of zinc-enzyme inhibitors and activators, the extensive use of X-ray crystallography and QSAR studies for understanding zinc-containing proteins, and clinical applications."

"Current pharmaceutical and clinical approaches to the treatment of disease suffer from the inherent limitations in the specialization of drugs introduced to physiological systems. The interface of clinical and material sciences has allowed for a broad spectrum of creative approaches with the potential to alleviate these shortcomings. However, the synergy of these disciplines also presents problems in which nascent technology lacks the necessary evaluation within its intended clinical environment. Given the growing potential for materials science to address a number of unanswered therapeutic needs, it remains even more pressing to validate emerging drug delivery technologies in actual clinical environments. This book addresses the core fundamentals of drug delivery using material science and engineering principles, and then applies this knowledge using prominent examples from both the scientific literature and clinical practice"