We present a de novo design program called SYNOPSIS, that includes a synthesis route for each generated molecule. SYNOPSIS designs novel molecules by starting from a database of available molecules ...and simulating organic synthesis steps. This way of generating molecules imposes synthetic accessibility on the molecules. In addition to a starting database, a fitness function is needed that calculates the value of a desired property for an arbitrary molecule. The values obtained from this function guide the design process in optimizing the molecules toward an optimal value of the calculated property. Two applications are described. The first uses an electric dipole moment calculation to generate molecules possessing a strong dipole moment. The second makes use of the three-dimensional structure of a viral enzyme in order to generate high affinity ligands. Twenty eight compounds designed with the program resulted in 18 synthesized and tested compounds, 10 of which showed HIV inhibitory activity in vitro.
This paper reports the synthesis and the antiviral properties of new diarylpyrimidine (DAPY) compounds as nonnucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis program around this ...new DAPY series was further optimized to produce compounds displaying improved activity against a panel of eight clinically relevant single and double mutant strains of human immunodeficiency virus type 1 (HIV-1).
Human immunodeficiency virus type-1 integrase is an essential enzyme for effective viral replication and hence a valid target for the design of inhibitors. We report here on the design and synthesis ...of a novel series of phthalimide analogues as integrase inhibitors. The short synthetic pathway enabled us to synthesize a series of analogues with a defined structure diversity. The presence of a single carbonyl−hydroxy−aromatic nitrogen motif was shown to be essential for the enzymatic activity and this was confirmed by molecular docking studies. The enzymatically most active compound from this series is 7-(3,4-dichlorobenzyl)-5,9-dihydroxypyrrolo3,4-gquinoxaline-6,8-dione (15l) with an IC50 value of 112 nM on the HIV-1 integrase enzyme, while ((7-(4-chlorobenzyl)-5,9-dihydroxy-pyrrolo3,4-gquinoxaline-6,8-dione (15k)) showed an EC50 of 270 nM against HIV-1 in a cell-based assay.
A series of novel pyrazinones designed as non-nucleoside reverse transcriptase inhibitors (NNRTIs) was synthesized and their anti-HIV structure−activity relationship (SAR) was studied.
The synthesis and anti-HIV-1 activity of a series of diarylpyrimidines (DAPYs) are described. Several members of this novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) are ...extremely potent against both wild-type and a panel of clinically significant single- and double-mutant strains of HIV-1.
The synthesis and anti-HIV-1 activity of a series of diarylpyrimidines (DAPYs) are described. Several members of this novel class of NNRTIs display excellent potency against both the wild-type and single- and double-mutant strains of the HIV-1 virus.
Application of boosting to both two-class and multi-class classification problems are studied. Five real chemical data sets are used. Each data is randomly divided into two subsets, one for training ...and the other for prediction. For two-class classification, each data is separated into a high response level class and a low response level class according to a threshold value. As a result, three data sets, wheat data, cream data and HIV data, show that boosting using classification and regression trees (CART) as a base learner may decrease the misclassification rate in prediction with respect to using a single CART. However, boosting for green tea data indicates that overfitting may occur when boosting is applied. For the chromatographic retention data, boosting performs worse than a single CART. The cream data and the HIV data are also used for multi-class classification. Both data sets demonstrate that boosting performs better than CART in multi-classification. Variable importance analysis suggests that the improvement made by boosting may be due to the use of more variables, which give more information on special types of samples in the training data.
We have developed a fast and robust computational method for prediction of antiviral activity in automated de novo design of HIV-1 reverse transcriptase inhibitors. This is a structure-based approach ...that uses a linear relation between activity and interaction energy with discrete orientation sampling and with localized interaction energy terms. The localization allows for the analysis of mutations of the protein target and for the separation of inhibition and a specific binding to the enzyme. We apply the method to the prediction of pIC50 of HIV-1 reverse transcriptase inhibitors. The model predicts the activity of an arbitrary compound with a q 2 of 0.681 and an average absolute error of 0.66 log value, and it is fast enough to be used in high-throughput computational applications.
In this article, the application of Multivariate Adaptive Regression Splines (MARS) for modelling the biological activity of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) is described. The ...studied data consist of the biological activities of 208 NNRTIs evaluated against wild-type HIV virus (HIV-1) and four mutant strains (181C, 103N, 100I, 188L), and the computed interaction energies with the amino acids forming the NNRTI binding pocket. The NNRTIs belong to five different chemical classes of compounds, known as HEPT-like, TIBO, DATA, DAPY and ITU compounds. The MARS model obtained for the biological activity of NNRTIs yields acceptable prediction errors for this data set.
A synthesis program directed toward improving the stability of imidoyl thiourea based non-nucleoside reverse transcriptase inhibitors (NNRTIs) led to the discovery of diaryltriazines (DATAs), a new ...class of potent NNRTIs. The synthesis and anti-HIV structure-activity relationship (SAR) studies of a series of DATA derivatives are described.
PDF
