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Current Computer-aided Drug Design

Bishnupriya Panda, Babita Majhi, Abhimanyu Thakur
BACKGROUND: Proteins are the utmost multi-purpose macromolecules, which play a crucial function in many aspects of biological processes. For a long time, sequence arrangement of amino acid has been utilized for the prediction of protein secondary structure. Besides, in major methods for the prediction of protein secondary structure, impact of the Gaussian noise on sequence representation of amino acids has not been considered until now; which is one of the important constraints for the functionality of a protein...
August 27, 2018: Current Computer-aided Drug Design
Proyasha Roy, Sumanta Dey, Ashesh Nandy, Subhash C Basak, Sukhen Das
Among the mosquito-borne human-infecting flavivirus species that include Zika, West Nile, yellow fever, Japanese encephalitis and Dengue viruses, the Zika virus is found to be closest to Dengue virus, sharing the same clade in the Flavivirus phylogenetic tree. We consider these five flaviviruses and on closer examination in our analyses, the nucleotide sequences of the Dengue viral genes (envelope and NS5) and genomes are seen to be quite widely different from the other four flaviviruses. We consider the extent of this distinction and determine the advantage and/or disadvantage such differences may confer upon the Dengue viral pathogenesis...
July 30, 2018: Current Computer-aided Drug Design
Maryam Nazari, Sayyed Abbas Tabatabai, Elham Rezaee
Acetylcholinesterase enzyme (AChE) is the main target in Alzheimer's disease therapy and designing of novel AChE inhibitors is a great deal of attention. In this study, 2D-QSAR and 3D-QSAR models were generated using stepwise multiple linear regressions (SW-MLR) and comparative molecular field analysis (CoMFA) respectively. It was found that CoMFA model with r² of 0.947 for the training set and r² of 0.816 for the test set is more favorable than model which is established by SW-MLR method with r² =0.825 and r²pred =0...
July 25, 2018: Current Computer-aided Drug Design
Nupur S Munjal, Manu Sharma, Tiratha Raj Singh
QSPR modelling is one of the major computational tools used to correlate molecular characteristics with physiochemical properties of molecules. In present work, QSPR models are formed using AIC and VIF multicollinearity indicators for descriptors selection taking solubility data of Paclitaxel derivatives. Geometry optimization of these Paclitaxel derivatives was performed at two basis sets (PM6 and AM1) using Gaussian software. Four descriptor groups such as 2D Autocorrelation, CATS_3D, WHIM, GETAWAY provided initial QSPR models with moderate accuracy for both the optimized geometry datasets...
July 12, 2018: Current Computer-aided Drug Design
Thomas Wein, Klaus T Wanner, Sebastian Rappengluck, Sonja Sichler, Karin V Niessen, Thomas Seeger, Franz Worek, Horst Thiermann
Irreversible inhibition of the acetylcholinesterase upon intoxication with organophosphorus compounds leads to an accumulation of acetylcholine in the synaptic cleft and a subsequent desensitization of nicotinic acetylcholine receptors which may ultimately result in respiratory failure. A direct intervention at the nicotinic acetylcholine receptor nAChR was proposed as an alternative therapeutic approach to the treatment with atropine and oximes. The bispyridinium compound MB327 has been found to recover functional activity of nAChR thus representing a promising starting point for the development of new drugs for the treatment of organophosphate poisoning...
July 3, 2018: Current Computer-aided Drug Design
Md Mostafijur Rahman, Md Bayejid Hosen, M Zakir Hossain Howlader, Yearul Kabir
BACKGROUND: 3C-like protease also called the main protease is an essential enzyme for the completion of the life cycle of Middle East Respiratory Syndrome Coronavirus. In our study we predicted compounds which are capable of inhibiting 3C-like protease,and thus inhibit the lifecycle of Middle East Respiratory Syndrome Coronavirus using in silico methods. METHODS: Lead like compounds and drug molecules which are capable of inhibiting 3C-like protease was identified by structure-based virtual screening and ligand-based virtual screening method...
June 29, 2018: Current Computer-aided Drug Design
Neeraj Masand, Satya P Gupta, Ratan Lal Khosa
INTRODUCTION: A novel series of multifunctional anti-Alzheimer's agents based on N-substituted aryl sulphonamides were designed and synthesized. During in vivo moderate to good anti-Alzheimer's disease (AD) activity was observed as correlated by the modulation of some selected biochemical markers of AD as well as during behavioral assessment. METHODS: Among the series, some compounds have shown multi-functional potency by inhibition of acetylchlinesterase (AChE), Scopolamine induced oxidative stress and were found comparable to the standard drug (Donepezil, 50µg/kg, i...
June 3, 2018: Current Computer-aided Drug Design
Huan-Yu Meng, Wan-Lin Jin, Cheng-Kai Yan, Huan Yang
The development of a novel drug is an extremely complicated process that includes the target identification, design and manufacture, and proper therapy of the novel drug, as well as drug dose selection, drug efficacy evaluation, and adverse drug reaction control. Due to the limited resources, high costs, long duration, and low hit-to-lead ratio in the development of pharmacogenetics and computer technology, machine learning techniques have assisted novel drug development and have gradually received more attention by researchers...
May 25, 2018: Current Computer-aided Drug Design
Belgin Sever, Kaan Kucukoglu, Hayrunnisa Nadaroglu, Mehlika Dilek Altintop
BACKGROUND: Paraoxonase 1 (PON1) is a paraoxonase, arylesterase and lactonase associated with protection of lipoproteins and cell membranes against oxidative modification. OBJECTIVE: Based on antioxidative properties of PON1 and widely usage of 1,3,4-thiadiazole derivatives in pharmaceutical, agricultural, and materials chemistry, herein we aimed to evaluate PON1 activator potentials of 1,3,4-thiadiazole based compounds. METHOD: 2-[[5-(2,4-Difluoro/dichlorophenylamino)-1,3,4-thiadiazol-2-yl]thio] acetophenone derivatives (1-18), previously synthesized by our research group, were in vitro evaluated for their activator effects on PON1 which was purified using ammonium sulfate precipitation (60-80%) and DEAE-Sephadex anion exchange chromatography...
May 17, 2018: Current Computer-aided Drug Design
Agha Zeeshan Mirza, Hina Shamshad
QSAR models as PLS, GFA, and 3D were developed for series of matriptase inhibitors using 35 piperidyl-cyclohexylurea compounds. The training and test sets were divided into a set of 28 and 8 compounds, respectively and the pki values of each compound were used in the analysis. Docking and alignment methodologies were used to develop models in 3D QSAR. The best models among all were selected on the basis of regression statistics as r2, predictive r2 and Friedman Lack of fit measure. Hydrogen donors and rotatable bonds were found to be positively correlated properties for this target...
May 16, 2018: Current Computer-aided Drug Design
Atefeh Saadabadi, Babak Kohen, Maryam Irandoust, Hamed Shafaroudi, Tara Mohammadpour, Mahdi Rezayat, Asghar Davood
In this study, fifteenth new 2,5-disubstituted analgouges of phthalimide were designed and synthesized using the appropriate synthetic route to evaluate anticonvulsant activity against the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) compare to phenytoin as a positive control. The structures of the synthesized compounds were confirmed by FT-IR, H-NMR, C-NMR and MASS spectroscopy. All the tested compounds were found to be effective in the PTZ model at the dose of 60 mg/kg and most of the compounds showed protection against MES test indicative of their ability to inhibit the seizure spread at the all dose ranges...
May 15, 2018: Current Computer-aided Drug Design
Rucha R Wani, Hemchandra K Chaudhari
Docking and 3D QSAR studies were performed on Inhibitor of Bacterial DNA gyrase to develop a predictive Common Pharmacophore Hypothesis (CPH) and use it for alignment in PHASE; with a diverse set of 58 bacterial DNA gyrase inhibitors. A five point CPH with H-bond acceptor(A), Hydrophobic (H), Hydrogen bond Donor(D), Aromatic ring(R), a basic or positively ionizable feature. From them, the best pharmacophore hypothesis AAAPR gives a statistically significant and 3D QSAR model with 0.92 as R-squared value and 0...
May 15, 2018: Current Computer-aided Drug Design
Adewale J Ogunleye, Gabriel O Eniafe, Olumide K Inyang, Benjamin Adewumi, Olaposi I Omotuyi
Backgound: Inhibition of penicillin binding protein 2A (PBP2A) represents a sound drug design strategy in combatting Methicillin resistant Staphylococcus aureus (MRSA). Considering the urgent need for effective antimicrobials in combatting MRSA infections, we have developed a statistically robust ensemble of molecular descriptors (1, 2, & 3-D) from compounds targeting PBP2A in vivo. METHODS: 37 (training set: 26, test set: 11) PBP2A-inhibitors were submitted for descriptor generation after which an unsupervised, non-exhaustive genetic algorithm (GA) was deployed for fishing out the best descriptor subset...
May 15, 2018: Current Computer-aided Drug Design
Imran H Khan, Navin B Patel, Vatsal M Patel
BACKGROUND: A series of (E)-5-(4-((Z)-4-substitutedbenzylidene/2-thienylmethylene-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl) benzylidene)thiazolidine-2,4-dione were synthesized and evaluated for antimycobacterial and antimicrobial activity. All these ligands were docked against protein (InhA) Enoyl-ACP reductase of the type II fatty acid syntase (FAS-II) system, (PDB ID: 4COD). OBJECTIVE: In this report we have designed and synthesized azole scaffolds with good antitubercular activities as there is a real need to develop new candidates with less toxicity and more efficient toward pathogen...
May 15, 2018: Current Computer-aided Drug Design
Burak Tuzun, Sevtap Caglar Yavuz, Nazmiye Sabanci, Emin Saripinar
In the present work, pharmacophore identification and biological activity prediction for 86 pyrazole pyridine carboxylic acid derivatives were made using the electron conformational genetic algorithm approach which was introduced as a 4D-QSAR analysis by us in recent years. In the light of the data obtained from quantum chemical calculations at HF/6-311 G** level, the electron conformational matrices of congruity (ECMC) were constructed by EMRE software. Comparing the matrices, electron conformational submatrix of activity (ECSA, Pha) was revealed that are common for these compounds within a minimum tolerance...
May 13, 2018: Current Computer-aided Drug Design
Samawia Rizwan, Asim Mehmood, Irum Khalid, Muhammad Saad Khan, Qudsia Yousafi, Hayssam M Ali, Mohamed S Elshikh, Saima Kalsoom, Hamid Rashid
Polypharmacology is a design or use of pharmaceutical agents in which single drug is used to treat multiple diseases. Aquaporin proteins are identified to treat migraine with aura and brain edema. This study focuses on Aquaporin-1 and Aquaporin-4. AQP-1 is expressed in small afferent sensory nerve fibers. Over-expression of peripheral nervous system causes migraine. AQP-4 is an abundant channel water protein in brain that regulates water transport to prevent homeostasis. Over-expression of AQP-4 contributes to water imbalance in ischemic pathology resulting in cerebral edema...
May 13, 2018: Current Computer-aided Drug Design
Chandan Raychaudhury, Md Imbesat Hassan Rizvi, Debnath Pal
BACKGROUND: Generating a large number of compounds using combinatorial methods increases the possibility of finding novel bioactive compounds. Although some combinatorial structure generation algorithms are available, any method for generating structures from activity-linked substructural topological information is not yet reported. OBJECTIVE: To develop a method using graph-theoretical techniques for generating structures of antitubercular compounds combinatorially from activity-linked substructural topological information, predict activity and prioritize and screen potential drug candidates...
May 9, 2018: Current Computer-aided Drug Design
Preeti Patel, Vijay K Patel, Avineesh Singh, Talha Jawaid, Mehnaz Kamal, Harish Rajak
BACKGROUND: Histone deacetylase 1 (HDAC1) over expression is responsible for carcinogenesis by promoting epigenetic silence of tumour suppressor genes. Thus, HDAC1 inhibitors has came out as the potential therapeutic leads against multiple human cancers, as they can block the activity of particular HDACs, renovate the expression of several tumour suppressor genes and bring about cell differentiation, cell cycle arrest and apoptosis. METHODS: The present research work comprises of atom-based 3D-QSAR, docking, molecular dynamic simulations and DFT (density functional theory) studies on a diverse series of hydroxamic acid derivatives as selective HDAC1 inhibitors...
May 1, 2018: Current Computer-aided Drug Design
Subhabrata Majumdar, Subhash C Basak
BACKGROUND: Proper validation is an important aspect of QSAR modelling. External validation is one of the widely used validation methods in QSAR where the model is built on a subset of the data and validated on the rest of the samples. However, its effectiveness for datasets with a small number of samples but large number of predictors remains suspect. OBJECTIVE: Calculating hundreds or thousands of molecular descriptors using currently available software has become the norm in QSAR research, owing to computational advances in the past few decades...
April 26, 2018: Current Computer-aided Drug Design
Ashish D Patel, Rahul Barot, Inaxi Parmar, Ishan Panchal, Umang Shah, Mehul Patel, Bharat Mishtry
1,6-Dihydropyrimidine exerts notable pharmacological efficiency and emerged as integral backbones for treatment of type-II diabetes mellitus. To optimize the in vitro and in-silico study we carried out on substituted 1,6-Dihydropyrimidine. The objective of the present study is to evaluate the binding interaction of 1,6-Dihydropyrimidine compounds with protein tyrosine phosphatase (PTP1B) enzyme and also check ADME/T properties of best scored compounds. The in-silico study (docking) was carried out through target protein tyrosine phosphatase (PTP1B) retrieved from protein data bank having PDB ID: 2QBS and the anti diabetic activity of the test compounds was tested against protein tyrosine phosphatase (PTP1B) enzyme by using Calbiochem® PTP1B colorimetric assay kit...
April 26, 2018: Current Computer-aided Drug Design
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