Docking

Chikungunya viral RNA-dependent RNA polymerase (RdRp) activity is conferred by non structural protein 4 (nsp4), an important protein target towards the development of antiviral compounds. The present study deals about the development of homology model of nsP4 followed by molecular docking with known RdRp inhibitors experimented in Hepatitis C virus (HCV), HIV-1, Paramyxovirus, etc. The predicted catalytic site and two
allosteric binding sites were docked with nucleosidic and non-nucleosidic inhibitors. The best top five scoring ligands were selected based upon the interaction profiles and a common pharmacophore was developed. Further, RNA template-primer complex was docked within the template tunnel of modeled nsP4 to study the mode of polymerase activity.

The Bcr-Abloncoprotein with constitutive tyrosine kinase activity plays a pivotal role in the pathogenesis of chronic
myeloid leukemia (CML), therefore being an ideal target for the drug development. Imatinibmesylate, a selective
tyrosine kinases inhibitor (TKI), has excellent efficacy in the treatment of chronic myeloid leukemia. It has opened the
way to the development of additional TKIs against chronic myeloid leukemia, including nilotinib and dasatinib. In this
study, computational methods are used to design novel imatinib derivatives and evaluated them for interaction with the
Bcr-Abloncoprotein through insilico analysis by using Hyperchem 8.0, Gold 3.01 docking software. Here, from the
results, it is reported that 1, 14, 26, ligands are having dock score near to imatinib and modifications to these ligands
may result in better ligands than imatinib. The results of Toxicity studies also supported 1, 14, 26, better drug-likeness
properties. Ligand 4 has shown higher affinity and better interaction with Bcr-Abloncoprotein than imatinib and any
other newly designed molecules, but it had shown mutagenicity and irritancy.

Virtual screening (VS) is a powerful technique for identifying hit molecules as starting points for medicinal chemistry. The number of methods and softwares which use the ligand and target-based VS approaches is increasing at a rapid pace. What, however, are the real advantages and disadvantages of the VS technology and how applicable is it to drug discovery projects? This review provides a comprehensive appraisal of several VS approaches currently available. In the first part of this work, an overview of the recent progress and advances in both ligand-based VS (LBVS) and structurebased VS (SBVS) strategies highlighting current problems and limitations will be provided. Special emphasis will be given to in silico chemogenomics approaches which utilize annotated ligand-target as well as protein-ligand interaction databases and which could predict or reveal promiscuous binding and polypharmacology, the knowledge of which would help medicinal chemists to design more potent clinical candidates with fewer side effects. In the second part, recent case studies (all published in the last two years) will be discussed where the VS technology has been applied successfully. A critical analysis of these case studies provides a good platform in order to estimate the applicability of various VS strategies in the new lead identification and optimization.

One of the fundamental challenges in designing drug molecule against a disease target or protein is to predict binding affinity between target and drug or small molecule. In this review, our focus will be on advancement in the field of protein-small molecule interaction. This review has been divided into four major sections. In the first section, we will cover software developed for protein structure prediction. This will include prediction of binding pockets and post-translation modifications in proteins. In the second section, we will discuss software packages developed for predicting small-molecule interacting residues in a protein. Advances in the field of docking particularly advancement in the knowledge-based force fields will be discussed in the third part of the review. This section will also cover the method developed for predicting affinity between protein and drug molecules. The fourth section of the review will describe miscellaneous techniques used for designing drug molecules, like pharmacophore modelling. Our major emphasis in this review will be on computational tools that are available free for academic use.

A series of few triazole linked hydroxamic acid derivatives were designed virtually considering the basic
pharmacophore of suberoyl anilide hydroxamic acid (SAHA). The least energy conformers of each molecule was
generated and docked with human histone deacetylase (HDAC8) with PDB id 1T69 using Autodock 4.0.1. Most of the
molecules have shown significant binding interaction with the receptor. Among the test compounds, 1a and 1g have
shown highest free energy of binding -7.04 kcal/mol and -7.23 kcal/mol respectively, which is comparable to that of the
reference standard, SAHA

Molecular docking is a reliable method with which to identify the binding conformations of substrates, inducers and inhibitors of cytochrome P450 (CYP) enzymes. We used the docking method to explore possible binding modes of an entry inhibitor (maraviroc) and nonnucleoside reverse transcriptase inhibitors (delavirdine, efavirenz and etravirine) to cytochrome P450 3A4 (CYP3A4). In addition, docking results were compared with the binding conformations of HIV protease drugs to infer the binding site residues and potential drug–drug interaction profiles for combination therapy in the treatment of AIDS. We observed that efavirenz and etravirine induce metabolism of co-administered drugs by binding to a unique position in the active site of CYP3A4. Dosage adjustment is required for delavirdine and maraviroc when combined with HIV protease drugs. The present results are in good agreement with experimental data from drug interaction profiles. The information provided in this paper will be helpful in furthering our understanding the functions of CYP3A4, and could aid in the design of new drugs that would be metabolized easily without having any drug–drug interaction profile.

In spatial agent-based models (SABMs) each entity of the system being modeled is uniquely represented as an independent agent. Large scale emergent behavior in SABMs is population sensitive. Thus, the number of agents should reflect the system being modeled, which can be in the order of billions. Models can be decomposed such that each component can be concurrently processed by a different thread. In this thesis, a conceptual model for investigating parallelization strategies for SABMs is presented. The model, PPHPC, captures important characteristics of SABMs. NetLogo, Java and OpenCL (CPU and GPU) implementations are proposed. To confirm that all implementations yield the same behavior, their outputs are compared using two methodologies. The first is based on common model comparison techniques found in literature. The second is a novel approach which uses principal component analysis to convert simulation output into a set of linearly uncorrelated measures which can be analyzed in a model-independent fashion. In both cases, statistical tests are applied to determine if the implementations are properly aligned. Results show that most implementations are statistically equivalent, with lower-level parallel implementations offering substantial speedups. The PPHPC model was shown to be a valid template model for comparing SABM implementations.

In this study, Quantitative Structure-Activity/property relationships (QSAR/QSPR) by means of multiple linear regressions (MLR) was performed to investigate the relationship between the 48 compounds of Temephos (Tem) drivatives and their bioactivities against acetylcholinesterase (AChE) of Tribolium castaneum. Two compounds Propylene-N, N’-bis (O, O’-di Ethyl Phosphorothioat (12) and Ethylene N, ’N- di Methyl bis (O, O’di Phenyl Phosphoramidate (24) had the most mortality on the T. castaneum. The compound 24 (IC50
=34.54 ppm) is a good
alternative to Tem. Also, QSAR calculations indicated that the electrostatic characteristics of the most effective insecticide are applied. In docking data, Tem derivatives with the backbone of P (O)-NHP(O), P(O)-NH-NHP(O) and P(O)-XP(O) are located in the active site gorge of both AChE and butyrylcholinesterase (BChE) so as to maximize the favorable contacts. These compounds relate to enzymes by non-covalent interactions such as hydrogen bonding, electrostatic and hydrophobic (as Trp82 and Trp286). Also, these cannot reach the end of the hole because of compounds are locked in the middle between the peripheral and acyl pocket site in AChE and BChE enzymes. The results of MLR and GA-QSAR/QSPR model of human ChE showed that topological parameters affect the inhibitory potencies of the compounds on both of logK and p(IC50 and p(IC50
) results have a good linear relationship.

The aim of this work was to test the application of multi-walled carbon nanotube based molecularly imprinted polymer (MWCNTs-MIP) for the determination of dopamine (DA) in blood serum and urine samples. The acrylamide grafted MWCNTs with vinyl group (MWCNTs-g-AAm-CH=CH2) was prepared by free radical graft copolymerization technique. MIP was synthesized by selective polymerization of MWCNTs-g-AAm-CH=CH2 with itaconic acid (IA) as functional monomer in the presence of DA using ethylene glycol dimethacrylate (EGDMA) as a cross-linker and α,α’-azobisisobutyronitrile (AIBN) as the initiator. The response time was ~2 min and the detection limit was 1.0 × 10-9 mol L-1, so the proposed sensor could be considered as a sensitive marker of DA depletion in Parkinson's disease. The MWCNTs-MIP sensor demonstrated a high selectivity, sensitivity and stability, in addition to that good reproducibility. The useful lifetime for the DA sensor was longer than 2 months and the sensor was successfully tested in real samples.

Alzheimer's disease (AD) is the most common form of dementia in adults, which is characterized by senile plaquets and cholinergic deficit as the disease progresses. Improvement of cholinergic neurotransmission is the basis of some drugs currently used in the treatment of AD. It is ...

Curcumin has been reported to be therapeutically active but has poor bioavailability, half life, and high rate of metabolic detoxifcation. Most of the hydrophobic and acidic drugs get transported through human serum albumin (HSA). Binding of drugs to serum protein increases their half-life. The present study is focused to analyze interaction of curcumin with HSA by NMR and docking studies. In order to investigate the binding affinity of curcumin with HSA, NMR based diffusion techniques and docking study have been carried out. We report that curcumin has shown comparable binding affinity value vis-a-vis standard, the accessible surface area (ASA) of human serum albumin (uncomplexed) and its docked complex with curcumin at both binding sites was calculated and found to be close to that of warfarin and diazepam respectively. Conclusion drawn from our study demonstrates that curcumin interacts with HSA strongly thereby its poor half life is due to high rate of its metabolic detoxification as reported in literature. In diffusion NOE process the signals of small molecules remain (tryptophan and curcumin) which interact with macromolecules. However, the signals of molecules which do not interact disappear. This indicates curcumin and tryptophan molecule bind with human serum albumin

Mutu Dewasa ini sistem yang terdapat di dalam organisasi dapat mempengaruhi pelanggan untuk mencoba produk baru yang ditawarkan organisasi, dan kemudian tetap setia untuk terus memakai produk yang ditawarkan organisasi terebut. Semakin mudah pelanggan untuk mendapatkan produk yang ditawarkan organisasi melalui kemudahan sistem yang ada, semakin setia pula pelanggan memakai produk yang ditawarkan organisasi tersebut. Oleh karena itu, terdapat suatu standar untuk sistem yang diterapkan oleh manajemen, semakin baik sistem yang diterapkam manajemen dalam organisasi, maka semakin mudah bagi organisasi untuk mendapatkan standar Internasional bagi penerapan sistem manajemen di dalam organisasinya. ISO 9001:2000 adalah suatu standar internasional untuk sistem manajemen mutu. ISO 9001:2000 menetapkan persyaratan-persyaratan dan rekomendasi untuk desain dan penilaian dari sistem manajemen mutu. Manajemen mutu dapat dianggap memiliki tiga komponen utama: pengendalian mutu, jaminan mutu dan perbaikan mutu. Manajemen mutu berfokus tidak hanya pada mutu produk, namun juga cara untuk mencapainya. Manajemen mutu menggunakan jaminan mutu dan pengendalian terhadap proses dan produk untuk mencapai mutu secara lebih konsisten. b. Pengendalian Mutu dalam Proses Pengedokan Kapal Docking Kapal adalah suatu peristiwa pemindahan kapal dari air/laut ke atas dock dengan bantuan fasilitas docking/pengedockan. Untuk melakukan pengedokan kapal ini, harus dilakukan persiapan yang matang dan berhati-hati mengingat spesifikasi kapal yang berbeda-beda. Mengingat besarnya biaya yang dikeluarkan pihak owner dalam melakukan proses repair/perbaikan kapal. Maka diperlukan perhatian serius dalam proses memasukkan kapal naik ke dry dock. Hal ini dikarenakan saat-saat kapal yang paling ekstrem adalah pada saat setengah badan kapal kering dan setengah basah. Kehati-hatian dengan tetap mempertahankan kualitas mutu merupakan kunci dari proses pengedokan yang sukses. Standar mutu yang baik perlu disiapkan oleh pihak galangan dan owner demi kelancaran proses dari awal kapal datang ke galangan sampai naik 100 persen ke atas dok. Grafik flowchart proses administrasi dan doking repair kapal di galangan

KD PERANTAU menaiki galangan pada beban keseluruhan melebihi +-300 tan (air dan lumpur) drpd deadweight. Lebihan bebanan ini di buang secara berperingkat dan selesai lebih kurang 3 minggu selepas berada di atas galangan. Soalan saya. Adakah lebihan bebanan ni menjejaskan struktur kapal? Sekiranya ya, apakah cadangan Encik Muzammil utk saya bangkitkan isu ini kpd Boustead? Answers: In principal, vessels are designed to operate at her "max global hull girder bending moment and shear force limits It means that the vessel principle global and local strength shall withstand: Component of Min. Vessel's strength (global+local) = Hull girder bending moment (BM) and shear strength(S) = Static loads + dynamic loads = [(Internal load + external load)] + [(wave+ wind load)] = [(displacement load + static sea pressure)] + [(wave+ wind load)] Where: Vessel displacement load, = max design total weight = max design lightweight (LW) + deadweight (DW)

Resumen Context: Nyctanthes arbor-tristis L. (Oleaceae) leaf are used in treatment of malaria, rheumatoid arthritis, chronic fever and enlargement of spleen; however, there is paucity of information on its hepatoprotective and antioxidant potential. Aims: To evaluate hepatoprotective and antioxidant potentials of ethanolic leaf extract of Nyctanthes arbor-tristis L. Methods: After collection and authentication of the vegetal material, ethanolic extract was collected. The combination of antitubercular drugs (isoniazid, rifampicin and pyrazinamide) was used to induce hepatotoxicity in Wistar rats. Hepatoprotective effect was evaluated at doses 125, 250 and 500 mg/kg, body weight by estimating the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and levels of total bilirubin (TBL). The effects on lipid peroxidation (LPO), reduced glutathione (GSH) and catalase (CAT), superoxide dismutase (SOD) were estimated. Docking study was conducted to anticipate the probable biological targets associated with its hepatoprotective effect. Results: The plant extract dose of 500 mg/kg, body weight significantly declined the levels of AST, ALT, ALP and TBL at (p < 0.001), which is approximately corresponding to the dose of reference compound silymarin and reversed the levels of LPO, GSH, SOD, CAT as compared to silymarin dose. Histopathological studies revealed regeneration of hepatocytes. The docking results suggested that some active constituents of plant leaves potentially interact with human pregnane X receptor, human constitutive androstane receptor and the farnesoid X receptor. Conclusions: The extract of Nyctanthes arbor-tristis L. remarkably possesses hepatoprotective and antioxidant effect and evinced its traditional claim. Future studies should be done to isolate active phytoconstituents for use in drug discovery.

Alzheimer’s disease (AD) is most common form of dementia affecting elderly people, and sixth leading cause of death worldwide. The two abnormal structures formed in AD patient’s brain are beta-amyloid plaques and neurofibrillary. The beta-amyloid plaque formation is accelerated due to acetylcholinestarases. Treatment of AD has majorly dependent on inhibition of acetylcholinestarase. In the present study, acetylcholinesterase receptor is docked with solanine and its derivatives and with a commercially available drug. The lead 3 compounds, are selected based on minimum binding energy and interaction with the active site of the receptor, are much better compared to commercially available drug. Molecular interactions of the receptor complexes with lead solanine compounds are also found to be higher in number. By this it can be hypothesize that solanine derivatives can inhibit acetylcholinesterase more effectively, which controls rapid breaking of acetylcholine, a neurotransmitter to acetyl and choline and aid in Alzheimer’s treatment.

Present communication deals with the docking study of hybrid phenyl thiazolyl-1,3,5-triazine analogues (1a–36d) on three selected different binding site viz., α, β and γ of wild type Pf-DFHR-TS. In admiration of excellent H-bond scoring, with regard to cycloguanil and to a large extent similar scoring with WR99210, compound 4a, 12b, 21c, 23c, 28d, 29d, 34d, and 35d were selected for in vitro antimalarial activity against 3D7 strain of Plasmodium falciparum. Findings from the study disclose that a significant correlation was exist between in vitro results and in silico prediction (r2 = 0.543). Furthermore, investigation of structure–activity relationships elucidate crucial structural requirement for site specific binding of ligands.

Background: Aspergillus fumigatus is the most common causative agent of invasive fungal infection in immunosuppressed individuals. These include patients receiving immunosuppressive therapy for autoimmune or neoplastic disease, organ transplant recipients, and AIDS patients. A. fumigatus is the primary cause of invasive infection in the lungs and represents a major cause of morbidity and mortality in infected individuals. Additionally, A. fumigatus can cause chronic pulmonary infections, allergic bronchopulmonary aspergillosis, or allergic disease in immunocompetent hosts. Falcarindiol is a polyacetylene found in carrot roots which has antifungal activity.

Vinblastine (VLB), a cytotoxic alkaloid is used extensively against various cancer types and the crystal structure of its tubulin complex is already known. Multitarget affinity of vinblastine has been investigated and the nature of binding with biological receptors namely, duplex DNA and Human serum albumin (HSA) has been compared to the binding characteristics of its known complex with natural high affinity receptor tubulin using molecular docking and QM–MM calculations. VLB is found to interact with DNA as well as HSA protein, though, with weaker affinity as compared to tubulin. Analysis of various docked complexes revealed that the H-bonds and cation–pi bonds do not have significant contribution to the binding interactions and despite its large size, VLB remains in relaxed conformation and fits in the hydrophobic regions on the receptors.

Context: Bacterial resistance to antibiotics is the inevitable consequence of the use of antimicrobial agents. Thus, quinolones are an important class of antibacterials; these agents generally consist of a 1-subtituted-1,4-dihydro-4-oxopyridine-3-carboxylic acid moiety combined with an aromatic or heteroaromatic ring fused at the 5-and 6-position. Aims: To determine the binding of quinolones to DNA gyrase of Escherichia coli. Methods: An analysis was performed using an in silico approach to determine, by docking calculations and energy descriptors, the conformer of 4‐oxo‐1,4‐dihydroquinoline skeleton that forms the most stable complex with DNA gyrase of E. coli. Results: The complex shows that the pose of the quinolones coincides with the amino acid residues Asp87, Thr88, Arg91 and Met92, which is expected to be critical in the binding of quinolones to DNA gyrase of E. coli. A series of quinolones were computationally designed, and the interactions between the quinolones and the amino acid residues of the DNA gyrase were calculated. Conclusions: Among the designed compounds, compounds 105 and 115 exhibit higher binding energy values and interact with amino acids Asp87, Thr88, Arg91 and Met92.