Hasil Pencarian  ::  Simpan CSV :: Kembali

Abstrak :
ABSTRACT
One of the processes requiring HPC environments is Molecular Dynamics ( MD ) . In tropical countries, the MD process is very important in the preparation of virtual screening experiments for anti-malaria search. Previous works on the virtual screening project for anti-malaria search conducted by WISDOM project uses grid infrastructure with 1,700 CPUs of various infrastructure provided in 15 countries [13]. In silico anti malaria compounds searching from Indonesian medical plants using virtual screening methods are urgently required. This can reduce the cost and time required compared to the direct searching or examining each compound by in vitro and in vivo which will spend a lot of time and expense . However, the use of thousands of processors is difficult for the researchers with limited resources in developing countries such as Indonesia. Our of previous studies using MD with GROMACS shows the improvement of the simulation time using Cluster. But that is not the case for some of our previous works with AMBER on Cluster where we did not obtain significant speed up. However, our previous works running GROMACS on GPUs provided significant speed up about 12 times faster than that run on Cluster. In this study , we build a GPU -based computing environment and have some MD simulation with AMBER. We used several computing environments such as cluster with 16 cores , GPU Geforce GTX 465 , GTX 470 , GTX 560 , GTX 680 , and GTX 780 . In addition to PfENR ( Plasmodium falciparum Enoyl acyl Carrier Protein Reductase ) enzyme , as benchmark we also conducted MD experiments on Myoglobin protein , Dihydrofolate reductase (DHFR) protein, and Ras - Raf protein . All experimental results showed that the slowest MD processes occurred on Cluster, followed in increasing order by GTX 560, GTX 465, GTX 470, GTX 680 and GTX 780. While the GPU speed up relative to cluster is about 24 , 26 , 32 , 24 , 77 and 101, respectively.

Abstrak :

Sirtuin 1 (SIRT1) adalah famili  kelas III dari protein histon deasetilasi (HDAC) dan reaksinya bergantung  dengan  NAD⁺. Aktivator SIRT1 menyerupai pembatasan kalori merupakan pendekatan terapi untuk diabetes mellitus tipe 2. Pencarian obat dapat dilakukan dengan metode  in silico untuk mempercepat dan memfasilitasi identifikasi kandidat senyawa terbaik dan karakteristik fisikokimia dan pemilihan hit-to-lead.

Penelitian ini bertujuan untuk mengeksplorasi dan mengidentifikasi senyawa tanaman obat yang menyerupai CR (calorie restriction mimetic) dari Basis Data Herbal Indonesia (HerbalDB) http://herbaldb.farmasi.ui.ac.id yang berpotensi sebagai kandidat untuk aktivator SIRT1  melalui kombinasi metode in silico dan in vitro. Pemodelan farmakofor diperoleh dengan dua cara yaitu  menggunakan ko-kristal yang terikat pada daerah allosterik SIRT1 dan senyawa-senyawa yang digunakan sebagai aktivator SIRT1. Kemudian, model ini digunakan untuk penapisan virtual dengan HerbalDB. Senyawa yang diperoleh diidentifikasi menggunakan penambatan molekul dengan program AutoDock4Zn dan simulasi dinamika molekul 50-ns menggunakan program Amber. Simulasi dinamika molekuler dianalisis menggunakan metode MM-GB(PB) SA. Senyawa yang terpilih diuji secara in vitro menggunakan uji luminesensi SIRT-Glo^TM.

Analisis interaksi ikatan antara ligan dan reseptor SIRT1 (PDB ID 4zzj dan 5btr) menunjukkan selektivitas ligan adanya interaksi hidrofobik pada Leu206, Ile223, Ile227. Interaksi ikatan hidrogen antara [Glu230 dengan Arg446] dan Arg234 (daerah allosterik) dengan Arg446, Val459, His473, Asp475 (daerah katalitik), karena adanya interaksi ini menjadi dekat ke arah daerah substrat. Hasil penapisan virtual menggunakan model farmakofor berbasis struktur adalah mulberrin dan model farmakofor berbasis ligan adalah gartanin, kuinidin dan kuinina sebagai prediksi terbaik aktivator SIRT1. Analisis In silico, perhitungan MM-GB(PB)SA mengkonfirmasi bahwa mulberrin, gartanin, kuinidin, kuinina menunjukkan interaksi ikatan pada daerah allosterik dan uji in vitro nilai EC₅₀ masing-masing adalah 2,10; 1,79; 1,71; 1,14μM. Jadi, dari studi in silico dan in vitro senyawa mulberrin, gartanin. kuinidin, dan kuinina, menjadi kandidat potensial untuk aktivator SIRT1.

 

---

Sirtuin 1 (SIRT1) is a class III family of protein histone deacetylases involved in NAD⁺-dependent deacetylation reactions. It has been suggested that SIRT1 activators, in a therapeutic approach for type 2 diabetes mellitus. Drug design can be performed in silico using molecular dynamic approaches to accelerate and facilitate identification of the best compound candidates and their physicochemical characteristics and hit-to-lead selection.

This study aimed to explore and identify medicinal plant compounds calorie restriction mimetic from Indonesian Herbal Database (HerbalDB) that might potentially become a candidate for SIRT1 activators through a combination of in silico and in vitro methods. Two pharmacophore models were developed using co-crystalized ligands that allosterically bind with SIRT1 similar to the putative ligands used by SIRT1 activators. Then, these were used for the virtual screening of HerbalDB. The identified compounds were subjected to molecular docking with the AutoDock4Zn program and 50-ns molecular dynamics simulation using the Amber program. Molecular dynamics simulation was analyzed using MM-GB(PB)SA methods.  The compounds identified by these methods were tested in an in vitro study using a SIRT-Glo^TM luminescence assay. Interaction analysis between activator ligand and the SIRT1 receptor (PDB IDs 4zzj and 5btr) revealed the ligand’s selectivity for hydrophobic interaction at Leu206, Ile223, Ile227. Hydrogen bond interactions between [Glu230 with Arg446] and Arg234 (allosteric region) with Val459, His473, and Asp475 (catalytic region) brought them close to the bounding substrate area. Virtual screening using structure-based pharmacophores predicted that mulberrin as the best candidate SIRT1 activator. Virtual screening using ligand-based pharmacophores predicted that gartanin, quinidine and quinine to be the best candidates as SIRT1 activators. The molecular docking studies showed the important residues involved were Ile223 and Ile227 at the allosteric region. The MM-GB(PB)SA calculations confirmed that mulberrin, gartanin, quinidine, quinine showed activity at allosteric region and their EC₅₀ in vitro values are 2.10; 1.79; 1.71; 1.14µM, respectively. Thus, mulberrin, gartanin, quinidine, and quinine, to be a potential candidate for SIRT1 activators.

 

Abstrak :
Tujuan dari penelitian ini adalah untuk mengamati interaksi molekular antara alfa glukosidase dari Saccharomyces cerevisiae dengan senyawa turunan sinamamid yang disintesis dari asam sinamat. Dalam penelitian ini, senyawa turunan sinamamid disintesis dan dievaluasi untuk penghambatan alfa glukosidase. Struktur senyawa yang disintesis diidentifkasi dengan IR, H-NMR, C-NMR dan Mass Spektral. Semua senyawa turunan sinamamid menunjukkan penghambatan potensial yang lebih unggul dari bahan awal. Tiga belas senyawa turunan sinamamid menunjukkan aktivitas alfa glukosidase dengan nilai IC50 0,71-4,0 mM dengan standar 1-deoksinojirimisin dan akarbosa IC50 =0,97 mM dan IC50=1,78 mM . Studi molecular docking dilakukan untuk mengeksplorasi interaksi pengikatan kandidat turunan sinamamid dengan enzim alfa glukosidase.

---

The aim of this study was to observe molecular interactions between alpha glucosidase from Saccharomyces cerevisiae with cinamamide derivatives which were synthesized by amidation of cinnamic acid. In this study, a series cinamamide derivatives was synthesized and evaluated for alpha glucosidase inhibitory. The structure of synthesized compounds were characterized by IR, H NMR, C NMR and Mass Spectral analysis. All compound cinamamide derivatives showed a potent inhibition superior to the starting material. Thirteen compounds showed alpha glucosidase activity with IC50 value of 0.71 4.02 mM with the standard 1 deoxynojirimycin and acarbose IC50 0,97 mM and IC50 1.78 mM, respectively . Molecular docking studies were carried out to explore the binding interactions of cinnamamide derivative candidates with enzyme alpha glucosidase.

Abstrak :
Protein inti virus hepatitis B memegang peranan penting pada berbagai tahap siklus hidup virus. Dengan mengganggu peran protein inti ini oleh suatu senyawa maka replikasi virus akan terhambat. Emodin dipilih sebagai senyawa penuntun dan dilakukan modifikasi struktur dengan mengubah sifat hidrofobisitas, elektronik dan steriknya. Untuk memprediksi interaksi yang terjadi antara emodin dan senyawa turunan ester emodin dengan protein inti virus hepatitis B sebagai target obat, dilakukan pemodelan molekul dengan program simulasi penambatan dan dinamika molekul. Interaksi senyawa turunan ester emodin dengan reseptor protein inti virus hepatitis B terjadi di daerah antarmuka dimer-dimer reseptor dan membentuk interaksi yang stabil dengan asam amino pada daerah yang akan mengubah konformasi protein sehingga mengganggu perakitan kapsid dan proses replikasi virus. Senyawa turunan ester emodin disintesis dengan pereaksi dan kondisi yang sesuai kemudian dikonfirmasi strukturnya menggunakan spekrofotometri LCMS/MS, FTIR, 1H-NMR dan 13C-NMR. Senyawa yang diperoleh adalah: 3-asetil emodin, 3-benzoil emodin, 3-o-toluil emodin, 3-m-toluil emodin, 3-p-toluil emodin dan 3-dimetilkarbamoil emodin. Aktivitas inhibisi in vitro ditentukan menggunakan sel HepG2 yang ditransfeksi plasmid genom inti virus hepatitis B, immunositokimia dan fluorometri. Hasil menunjukkan bahwa turunan ester emodin aktivitasnya lebih tinggi dan sitotoksitasnya lebih rendah daripada emodin. Senyawa 3-o-toluil emodin, 3-m-toluil emodin dan 3-p-toluil emodin menunjukkan aktivitas yang tinggi dengan IC50 berturut-turut sebesar 0,4; 0,23 dan 0,11 M. Analisa hubungan struktur aktivitas menunjukkan bahwa hidrofobisitas dan sterik berkorelasi non linear dengan aktivitas inhibisi replikasi virus hepatitis B.

---

The core protein of hepatitis B virus plays an important role at different stages of the viral life cycle. By disrupting the role of this core protein by a compound, the viral replication will be inhibited. Emodin was chosen as a lead compound and the structure was modified by altering its hydrophobicity, electronic and steric properties to be emodin ester. Prediction of interaction between emodin and their ester derivatives with hepatitis B virus core protein as drug targets, was performed by molecular modeling simulation program of docking and molecular dynamic. The interaction of emodin ester derivatives with hepatitis B virus core protein receptors occurs in the interface area of receptor dimers and forms a stable interaction with amino acids in areas that will alter protein conformation thus disrupting capsid assembly and viral replication processes. Emodin ester derivatives compound were synthesized with reagents and suitable conditions then confirmed their structures using LCMS MS, FTIR, 1H NMR and 13C NMR spectrophotometry. The compounds obtained were 3 acetyl emodin, 3 benzoyl emodin, 3 o toluyl emodin, 3 m toluyl emodin, 3 p toluyl emodin and 3 dimethylcarbamoyl emodin. In vitro inhibitory activity was determined using HepG2 cells transfected plasmid core genomes of hepatitis B virus, immunocytochemistry and fluorometry. The results showed that the emodin ester derivatives activity is higher and its cytotoxicity is lower than emodin. The 3 o toluyl emodin, 3 m toluyl emodin and 3 p toluyl emodin showed high activity with IC50 of 0.4 0.23 and 0.11 M respectively. Structure activity relationship analysis showed that hydrophobicity and steric properties correlate non linearly with activity.

Abstrak :
Senyawa turunan eugenol diduga dapat menginhibisi Bcl-2 pada sel kanker kolorektal HT29. Penelitian ini bertujuan untuk memperoleh senyawa baru turunan eugenol yang dapat menghambat sel kanker kolorektal HT29 secara in vitro dan menurunkan ekspresi Bcl-2 pada mencit yang mengalami pre-klamsia terhadap kolon secara in vivo. Penelitian ini diawali dengan melakukan desain senyawa turunan secara in silico. Hasil senyawa hit disintesis di laboratorium. Uji secara in vitro, uji apoptosis dan uji in vivo dilakukan berturut-turut pada hasil senyawa sintesis. Hasil in silico, dari skrining secara farmakofor dengan rancangan acak lengkap menggunakan 220 senyawa desain. Berdasarkan fitur farmakofor dengan cut off 5 fitur dihasilkan 23 senyawa. Hasil skrining farmakofor dilakukan docking menghasilkan delapan senyawa yaitu senyawa 4 rsquo;- 2-kloro-3-hidroksipropil -2 rsquo;-metoksifenil 2-hidroksibenzoat 57, 4 rsquo;- 2-kloro-3-hidroksi-propil -2 rsquo;-hidroksifenil 2-hidroksibenzoat 167, S -4 rsquo;- 2,3-dihidroksipropil -2 rsquo;-metoksifenil 2-hidroksibenzoat 59, R -4 rsquo;- 2,3-dihidroksipropil -2 rsquo;-metoksifenil 2-hidroksibenzoat 60, 4 rsquo;-alil-2 rsquo;-metoksifenil 4-amino-2-hidroksibenzoat 71, 4 rsquo;-alil-2 rsquo;-hidroksifenil 4-amino-2-hidroksibenzoat 181, 4 rsquo;-alil-2 rsquo;-metoksifenil 3,4,5-trihidroksibenzoat 86 dan 4 rsquo;-alil-2 rsquo;-metoksifenil 3,5-diihidroksi-4-metoksibenzoat 91 dengan energi ikatan lebih negatif dari standar. Delapan senyawa hasil skrining disintesis melalui reaksi esterifikasi, adisi halogen, hidroksilasi dan demetilasi. Hasil sintesis diuji aktivitas penghambatannya secara in vitro terhadap sel HT29 kanker kolon. Aktivitas penghambatan terhadap sel HT29 menunjukkan nilai IC50 antara 82.98 g/mL - 8.455 g/mL. Nilai IC50 tersebut lebih negatif dibandingkan senyawa penuntun eugenol. Hubungan Kuantitatif Struktur Aktivitas terhadap sel line HT29 menghasilkan persamaan Log 1/IC50 = -0.865-0.210 LogP 2 1.264 logP -0.994CMR n=10; r=0.706; SE:0.21; F=0.497, sig=7.86 . Persamaan menunjukkan variabel log P dan CMR berpengaruh terhadap IC50. Sifat hidrofobisitas log P lebih berperan dibandingkan dengan sifat sterik CMR . Hasil uji in vivo terhadap mencit Mus musculus menunjukkan senyawa turunan 59 memiliki nilai HE dan IHK mendekati kontrol positif. Peningkatan dosis pemberian menyebabkan peningkatan degradasi Bcl-2 pada jaringan mendekati kontrol normal. Hasil penelitian menunjukkan bahwa senyawa baru turunan eugenol 59 yang diperoleh dapat menghambat kanker kolorektal secara in vitro dan in vivo.

---

Compounds derived from eugenol are thought to inhibit Bcl 2 in HT29 colorectal cancer cells. The aim of this study was to obtain new compounds of eugenol derivatives that could inhibit in HT29 cell invitro test and decrease of Bcl 2 expression in mice pre clammed on colon with invivo test. This research begins by designing in silico derivative compounds. The result of the hit compound is synthesized in the laboratory. In vitro tests, apoptotic test and in vivo test were performed successively on the result of the synthesis compound. In silico yield, from a complete randomized pharmacophore screening using 220 design compounds. Based on the pharmacophore features with cut off 5 features produced 23 compounds. The results of pharmacophore screening conducted docking which yielded eight compounds of compound 4 rsquo 2 chloro 3 hydroxypropyl 2 rsquo metohoxyphenyl 2 hydroxybenzoat 57, 4 rsquo 2 chloro 3 hidroxy propyl 2 rsquo hydroxyphenyl 2 hydroxybenzoat 167, S 4 rsquo 2,3 dihydroxypropyl 2 rsquo methoxyphenyl 2 hydroxybenzoat 59, R 4 rsquo 2,3 dihydroxypropyl 2 rsquo methoxyphenyl 2 hydroxybenzoat 60, 4 rsquo allyl 2 rsquo methoxyphenyl 4 amino 2 hydroxybenzoat 71, 4 rsquo allyl 2 rsquo hydroxyphenyl 4 amino 2 hydroxybenzoat 181, 4 rsquo allyl 2 rsquo methoxyphenyl 3,4,5 trihydroxybenzoat 86 dan 4 rsquo allyl 2 rsquo methoxyphenyl 3,5 dihydroxy 4 methoxybenzoat 91 with energy binding more negative than standard. The eight compounds of the screening are synthesized by esterification reaction, addition with halogen, hydroxylation. And demetylation The synthesis results were tested in vitro inhibitory activity against HT29 colon cancer cells. The inhibitory activity against HT29 cells shows an IC50 value between 82.98 g mL 8,455 g mL. The value of IC50 is better than the eugenol guiding compound. Quantitative Relation of Structure Activity against cell line HT29 with equation Log 1 IC50 0.865 0.210 LogP 2 1.264 logP 0.994CMR n 10 r 0.706 SE 0.21 F 0.497, sig 7.86 . This equation showed that log P and CMR have effect with IC50. Hydrophobicity log P more of effect compared than steric parameters CMR . In vivo test of Mus musculus that showed compound derivative 59 based on HE and IHK values approaching positive control. Increased dosage of administration leads to an increase in Bcl 2 degradation in tissues near normal control. The results showed that the new compound derived eugenol 59 obtained can inhibit colorectal cancer in vitro and in vivo.

Abstrak :
Senyawa andrografolida, metabolit sekunder pada tumbuhan Sambiloto (Andrographis paniculata), diketahui memiliki aktivitas antiplasmodia 50% in vitro (IC50) < 10 μM, sehingga layak dijadikan sebagai senyawa pemandu di dalam pencarian dan pengembangan obat antimalaria secara rasional. Enzim farnesil difosfat sintase P. falciparum (PfFPPS) merupakan target yang valid untuk obat antimalaria. Tujuan umum penelitian ini adalah membuktikan membuktikan hipotesis bahwa senyawa turunan andrografolida, yang rancangan strukturnya diperoleh melalui optimasi interaksi maya andrografolida dengan enzim PfFPPS berdasarkan pose penambatan maya substrat dan inhibitornya, memiliki aktivitas antiplasmodia in vitro yang lebih tinggi daripada aktivitas antiplasmodia in vitro andrografolida dan tidak toksik terhadap sel manusia. Melalui optimasi interaksi maya andrografolida dengan enzim PfFPPS berdasarkan pose penambatan maya substrat dan inhibitornya, telah diperoleh rancangan struktur turunan andrografolida yang baru yang berpotensi menghambat enzim PfFPPS. Melalui reaksi esterifikasi terhadap senyawa andrografolida, diperoleh senyawa 3,14-andrografolidabis(4'-kloro)benzoat (18). IC50 senyawa 18 terhadap P. falciparum galur 3D7 adalah: 131,60 μM. Persentase pertumbuhan sel DLD-1 di bawah pengaruh senyawa 18 hingga konsentrasi 63,74 μM adalah lebih dari 100%. Dengan demikian, senyawa turunan andrografolida tersebut memiliki aktivitas antiplasmodia in vitro yang lebih rendah daripada aktivitas antiplasmodia in vitro andrografolida, namun tidak toksik terhadap sel manusia.

---

Andrographolide, a secondary metabolite of Sambiloto (Andrographis paniculata), has a 50% in vitro antiplasmodial activity (IC50) < 10 μM, that it is suitable as a lead compund in an antimalarial drug discovery and development. P. falciparum farnesyl diphosphate synthase (PfFPPS) is a valid target for antimalarial drug. The main objective of this research is to prove the hypothesis that andrographolide derivative, whose design was obtained throughout optimization of virtual interaction between andrographolide and PfFPPS based on the docking pose of its substrates and inhibitor, has a higher in vitro antiplasmodial activity than that of andrographolide and is not toxic towards human cells. Throughout optimization of virtual interaction between andrographolide and PfFPPS based on the docking pose of its substrates and inhibitor, design of novel andrographolide derivatives which are potential to inhibit PfFPPS was obtained. Throughout esterification on andrographolide, an andrographolide derivative was obtained: 3,14-andrographolidebis(4'-chloro)benzoate (18). IC50 of 18 against P. falciparum 3D7 was: 131.60 μM. Percentage of human DLD-1 cell growth under the influence of 18 up to 63.74 μM was more than 100%. Therefore, this andrographolide derivative has lower in vitro antiplasmodial activity than that of andrographolide, but is not toxic towards human cells.

Abstrak :
ABSTRACT
Molecular Dynamics (MD) is one of processes that requires High Performance Computing environments to complete its jobs. In the preparation of virtual screening experiments, MD is one of the important processes particularly for tropical countries in searching for anti-Malaria drugs. The search for anti-Malaria has previously conducted, for example by WISDOM project utilizing 1,700 CPUS. This computing infrastructure will be one of the limitation for country like Indonesia that also needs in silico anti malaria compounds searching from the country medical plants. Thus finding suitable and affordable computing environment is very important. Our previous works showed that our dedicated Cluster computing power with 16 cores performance better than those using fewer cores, however the GPU GTX family computing power is much better. In this study, we investigate further our previous experiment in finding more suitable computing environment on much better hardware specification of non dedicated Cluster computing and GPU Tesla. We used two computing environments, the first one is Barrine HPC Cluster of The University of Queensland which has 384 compute nodes with 3144 computing cores. The second one is Delta Future Grid GPU Cluster which has 16 computing nodes with 192 computing cores, each nodes equipped with 2 NVIDIA Tesla C2070 GPU (448 cores). The results show that running the experiment on a dedicated computing power is much better than that on non dedicated ones, and the GPU performance is still much better than that of Cluster.