Docking

Selecting near-native conformations from the immense number of conformations generated by docking programs remains a major challenge in molecular docking. We introduce DockRank, a novel approach to scoring docked conformations based on the degree to which the interface residues of the docked conformation match a set of predicted interface residues. DockRank uses interface residues predicted by partner-specific sequence homology-based protein–protein interface predictor (PS-HomPPI), which predicts the interface residues of a query protein with a specific interaction partner. We compared the performance of DockRank with several state-of-the-art docking scoring functions using Success Rate (the percentage of cases that have at least one near-native conformation among the top m conformations) and Hit Rate (the percentage of near-native conformations that are included among the top m conformations). In cases where it is possible to obtain partner-specific (PS) interface predictions from PS-HomPPI, DockRank consistently outperforms both (i) ZRank and IRAD, two state-of-the-art energy-based scoring functions (improving Success Rate by up to 4-fold); and (ii) Variants of DockRank that use predicted interface residues obtained from several protein interface predictors that do not take into account the binding partner in making interface predictions (improving success rate by up to 39-fold). The latter result underscores the importance of using partner-specific interface residues in scoring docked conformations. We show that DockRank, when used to re-rank the conformations returned by ClusPro, improves upon the original ClusPro rankings in terms of both Success Rate and Hit Rate. DockRank is available as a server at http://einstein.cs.iastate.edu/DockRank/.

Depression associated with poor general medical condition, such as post-stroke (PSD) or post-myocardial infarction (PMID) depression, is characterized by resistance to classical antidepressants. Special treatment strategies should thus be developed for these conditions. Our study aims to investigate the mechanism of action of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17), a recently designed thiadiazine derivative with putative neuro- and cardioprotective and antidepressant-like effects, using combined in silico (for prediction of the molecular binding mechanisms), ex vivo (for assessment of the neural excitability using c-Fos immunocytochemistry), and in vivo (for direct examination of the neuronal excitability) methodological approaches. We found that the predicted binding affinities of L-17 to serotonin (5-HT) transporter (SERT) and 5-HT3 and 5-HT1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT3 and 5-HT1A receptors, respectively. L-17 robustly increased c-Fos immunoreactivity in the amygdala and decreased it in the hippocampus. L-17 dose-dependently inhibited 5-HT neurons of the dorsal raphe nucleus; this inhibition was partially reversed by the 5-HT1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT3 and 5-HT1A receptors; the effects of L-17 on amygdaloid and hippocampal excitability might be mediated via 5-HT, and putatively mediate the antidepressant-like effects of this drug. Since L-17 also possesses neuro- and cardioprotective properties, it can be beneficial in PSD and PMID. Combined in silico predictions with ex vivo neurochemical and in vivo electrophysiological assessments might be a useful strategy for early assessment of the efficacy and neural mechanism of action of novel CNS drugs.

Total USD = USD 37, 753-Price difference if permanent repair carried out = USD45,800-37,753 = about USD8000.00 Soft patched 370mm L = 3390mm OD = 414mm Judgment: We anticipated that, during the last repair, machining down of sleeve up to its permissible tolerance (6mm) was not achievevable. It meant that, it was expected that though the sleeve is machined down up to the max permissible, the porosities (due to corrosion) still can't be removed. Thus, the sleeve was slightly machined down and its surfaces were smoothened by Belzona. 31/08/2014-afloat repair at accessible area only with DEVCON – minor patch-up-used spare seal-Belzona coating was in bad condition + broken – (detached)

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

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.

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.

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.

Setiap galangan pasti memiliki keuntungan dan kelemahan yang berbeda-beda. Sama halnya dengan GEMAK Shipyard, galangan ini tentunya mempunyai keuntungan dan kelemahan yang berbeda dengan galangan yang lain. Kelemahan tersebut dapat berupa buruknya material handling, kurangnya jumlah crane, dll. Maka, kami mencoba menjabarkan masing-masing kelebihan dan kelemahan galangan ini dan membuat solusi atas kelemahan-kelemahan yang ada, sehingga nilai ekonomis suatu galangan dapat meningkat seiring meningkatnya produktivitas galangan tersebut.

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)

Novel (thio)phosphoramidate derivatives based on piperidincarboxamide with the general formula of (NH 2 –C(O)–C 5 H 9 N)–P(X = O,S)R 1 R 2 (1–5) and (NH 2 –C(O)–C 5 H 9 N) 2 –P(O)R (6–9) were synthesized and characterized by 31 P, 13 C, 1 H NMR, IR spectroscopy. Furthermore, the crystal structure of compound (NH 2 –C(O)–C 5 H 9 N) 2 –P(O)(OC 6 H 5) (6) was investigated. The activities of derivatives on cholinesterases (ChE) were determined using a modified Ellman's method. Also the mixed-type mechanisms of these compounds were evaluated by Lineweaver–Burk plots. Molecular docking and quantitative structure– activity relationship (QSAR) were used to understand the relationship between molecular structural features and anti-ChE activity, and to predict the binding affinity of phosphoramido-piperidinecarboxamides (PAPCAs) to ChE receptors. From molecular docking analysis, noncovalent interactions especially hydrogen bonding as well as hydrophobic was found between PAPCAs and ChE. Based on the docking results, appropriate molecular structural parameters were adopted to develop a QSAR model. DFT-QSAR models for ChE enzymes demonstrated the importance of electrophilicity parameter in describing the anti-AChE and anti-BChE activities of the synthesized compounds. The correlation matrix of QSAR models and docking analysis confirmed that electrophilicity descriptor can control the influence of the hydrophobic properties of P = (O, S) and C@O functional groups of PAPCA derivatives in the inhibition of human ChE enzymes.

Human purine nucleoside phosphorylase (HsPNP) is a target for inhibitor development aiming at T-cell immune response modulation. In this work, we report the development of a new set of empirical scoring functions and its application to evaluate binding affinities and docking results. To test these new functions, we solved the structure of HsPNP and 2-mercapto-4(3H)-quinazolinone (HsPNP:MQU) binary complex at 2.7 Å resolution using synchrotron radiation, and used these functions to predict ligand position obtained in docking simulations. We also employed molecular dynamics simulations to analyze HsPNP in two conditions, as apoenzyme and in the binary complex form, in order to assess the structural features responsible for stability. Analysis of the structural differences between systems provides explanation for inhibitor binding. The use of these scoring functions to evaluate binding affinities and molecular docking results may be used to guide future efforts on virtual screening focused on HsPNP.

A series of novel purine and pyrimidine derivatives were prepared and biologically evaluated for their in vitro anti-CDK2/cyclin A3 and antitumor activities in Ehrlich ascites carcinoma (EAC) cell based assay. The novel purine derivatives 13a,b demonstrated potent inhibitor activities with IC50 values of 14 ± 9 and 13 ± 9 μM, respectively. Additionally, compound 15a showed the highest potency (IC50 = 10 ± 6 μM) in EAC cell based assay. Molecular modeling study, including fitting to a 3D-pharmacophore model and their docking into cyclin dependant kinase2 (CDK2) active site showed high fit values and docking scores.The manuscript describes the investigation of a series of novel purine and pyrimidine derivatives, which were prepared in good yield by using diaminomaleonitrile and tosylisocyanate in acetonitrile. Molecular modeling studies, including fitting to a 3D-pharmacophore model their docking into cycline-dependent kinase2 (CDK2) active site were performed to understand the structural features of CDK2 inhibitors. Biological evaluation for both in vitro CDK2/cyclinA3 inhibition activity and antitumor activity in Ehrlich ascites carcinoma (EAC) cell based assay were also carried out.

The title indolo-triazolo-pyrimidines were obtained from 3-azidoindoles and can be used as models for the design of DNA-interactive compounds. Hetero-domino reaction of azidoindoles/pyrroles and acetonitriles constitutes the synthetic entry to annelated 1,2,3-triazolo[1,5-a]pyrimidines.

Non-nucleoside reverse transcriptase inhibitors (NNRTI) has a definitive role and most commonly used in treatment of HIV infection. NNRTI act by binding to specific binding site (non-nucleoside binding pocket-NNBP) in reverse transcriptase (RT) enzyme. With the objective of developing efficient NNRTI, we have designed various Isatin analogs for effective treatment of AIDS and were subjected to molecular docking studies on five different crystal structures of RT complexed with five different ligands Nevirapine, Delaviridine, Efavirenz, Etravirine, and Rilpivirine. Combined dock-score of compound N21, N11, N23 was found to be comparable with standards indicated that Isatin analogs have good binding affinity for NNBP. Docking results suggested that these types of compounds could be binding in the NNRTI binding site in a similar mode to a known non-nucleoside inhibitors. ADME properties of Isatin analogs were also analyzed using Qikprop 2.5 tool of Schrodinger software.

In untraditional environments and unexpected situations, it is not always possible for a fixed-architecture robot to meet all the task requirements. Self-assembly enables free bodies to autonomously join together and complete a task that would otherwise not be achievable with the independent modules. The main theme of this thesis is to investigate the possibility of converting frail and inflexible mobile robots to a single flexible modular robot, and conversely, to split up a long and slow structure into separate fast modules. To prove the possibility of having such a system, we propose a novel connection mechanism, as well as a vision-based docking guidance system. This docking system along with a parking control algorithm allow single articulated- steering mobile robots to autonomously connect and disconnect. So, the concept of this work lies at the intersection between modular and wheeled mobile robotic systems. The goal is to improve the performance of mobile robots by autonomously changing their locomotion method to best fit the terrain conditions

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.

The reaction of o-phenylene diamine and ethyl oxamate is reinvestigated and led to 3-aminoquinoxalin-2(1H)-one rather than benzimidazole-2-carboxamide as was previously reported. The structure of the obtained quinoxaline has been confirmed by X-ray. The anti-tumor activity of synthesized quinoxalines 1–21 has been evaluated by studying their possible inhibitory effects on Epstein–Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Among the studied compounds 1–21, compounds 12, 8, 13, 18, 17 and 19, respectively, demonstrated strong inhibitory effects on the EBV-EA activation without showing any cytotoxicity and their effects being stronger than that of a representative control, oleanolic acid. Furthermore, compound 12 exhibited a remarkable inhibitory effect on skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter. The result of the present investigation indicated that compound 12 might be valuable as a potent cancer chemopreventive agent. Moreover, the molecular docking into PTK (PDB: 1t46) has been done for lead optimization of the aforementioned compounds as potential PTK inhibitors.Ligand interaction and the binding mode of compound 17 with c-kit receptor, it exhibited 3 H-bonds with the amino acids in C-kit two of them with CYS 673 and one with ASP 677, the hydrogen bonds formed colored in green.► New quinoxalines derivatives have been synthesized to evaluate their cancer chemopreventive activity. ► The inhibitory effects of compounds 1–21 on Epsteine Barr virus early antigen (EBV-EA) activation induced by TPA have been studied. ► The in vivo two-stage carcinogenesis test of compound 12 was studied. ► The synthesized compounds docked into c-kit protein-tyrosine kinase.

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.