A quant. structure activity relationship (QSAR) study is performed for modeling and prediction of oral bioavailabilities of 216 diverse set of drugs.After calculation and screening of mol. descriptors, linear and nonlinear models were developed by using multiple linear regression (MLR), artificial neural network (ANN), support vector machine (SVM) and random forest (RF) techniques.Comparison between statistical parameters of these models indicates the suitability of SVM over other models.The root mean square errors of SVM model were 5.933 and 4.934 for training and test sets, resp.Robustness and reliability of the developed SVM model was evaluated by performing of leave many out cross validation test, which produces the statistic of Q²_SVM = 0.603 and SPRESS = 7.902.Moreover, the chem. applicability domains of model were determined via leverage approach.The results of this study revealed the applicability of QSAR approach by using SVM in prediction of oral bioavailability of drugs.

01 Dec 2007·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Hologram QSAR model for the prediction of human oral bioavailability

Q3 · MEDICINE

Article

Author: Carlos A. Montanari ; Tiago L. Moda ; Adriano D. Andricopulo

A drug intended for use in humans should have an ideal balance of pharmacokinetics and safety, as well as potency and selectivity. Unfavorable pharmacokinetics can negatively affect the clinical development of many otherwise promising drug candidates. A variety of in silico ADME (absorption, distribution, metabolism, and excretion) models are receiving increased attention due to a better appreciation that pharmacokinetic properties should be considered in early phases of the drug discovery process. Human oral bioavailability is an important pharmacokinetic property, which is directly related to the amount of drug available in the systemic circulation to exert pharmacological and therapeutic effects. In the present work, hologram quantitative structure-activity relationships (HQSAR) were performed on a training set of 250 structurally diverse molecules with known human oral bioavailability. The most significant HQSAR model (q(2)=0.70, r(2)=0.93) was obtained using atoms, bond, connection, and chirality as fragment distinction. The predictive ability of the model was evaluated by an external test set containing 52 molecules not included in the training set, and the predicted values were in good agreement with the experimental values. The HQSAR model should be useful for the design of new drug candidates having increased bioavailability as well as in the process of chemical library design, virtual screening, and high-throughput screening.

01 Jun 2005·Journal of VirologyQ2 · MEDICINE

Cinanserin Is an Inhibitor of the 3C-Like Proteinase of Severe Acute Respiratory Syndrome Coronavirus and Strongly Reduces Virus Replication In Vitro

Q2 · MEDICINE

Article

Author: Chen, Lili ; Chen, Jing ; Jiang, Hualiang ; Gui, Chunshan ; Günther, Stephan ; He, Xichang ; Thiel, Volker ; Ludewig, Burkhard ; Chen, Kaixian ; Bai, Donglu ; Zou, Jianping ; Luo, Xiaomin ; Luo, Haibin ; Shen, Xu ; Yang, Yifu ; Scandella, Elke ; Yang, Yiming ; Yang, Qingang ; Drosten, Christian ; Shen, Jianhua

ABSTRACTThe 3C-like proteinase (3CLpro) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for anti-SARS-CoV drugs due to its crucial role in the viral life cycle. In this study, a database containing structural information of more than 8,000 existing drugs was virtually screened by a docking approach to identify potential binding molecules of SARS-CoV 3CLpro. As a target for screening, both a homology model and the crystallographic structure of the binding pocket of the enzyme were used. Cinanserin (SQ 10,643), a well-characterized serotonin antagonist that has undergone preliminary clinical testing in humans in the 1960s, showed a high score in the screening and was chosen for further experimental evaluation. Binding of both cinanserin and its hydrochloride to bacterially expressed 3CLproof SARS-CoV and the related human coronavirus 229E (HCoV-229E) was demonstrated by surface plasmon resonance technology. The catalytic activity of both enzymes was inhibited with 50% inhibitory concentration (IC50) values of 5 μM, as tested with a fluorogenic substrate. The antiviral activity of cinanserin was further evaluated in tissue culture assays, namely, a replicon system based on HCoV-229E and quantitative test assays with infectious SARS-CoV and HCoV-229E. All assays revealed a strong inhibition of coronavirus replication at nontoxic drug concentrations. The level of virus RNA and infectious particles was reduced by up to 4 log units, with IC50values ranging from 19 to 34 μM. These findings demonstrate that the old drug cinanserin is an inhibitor of SARS-CoV replication, acting most likely via inhibition of the 3CL proteinase.

100 Deals associated with Pirazolac

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Rheumatic Diseases	Italy	Mediolanum SpA	13 Aug 1995

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Rheumatic Diseases	Phase 1	-	Bayer AG	-
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Rheumatic Diseases	Phase 1	United States	Bayer HealthCare Pharmaceuticals, Inc.	-

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