A series of 46 dihydro-alkoxy-benzyl-oxopyrimidines （DABOs）, a class of highly potent non-nucleoside reverse transcriptase inhibitors （NNRTIs）, was studied by molecular docking followed by comparative molecular fi...A series of 46 dihydro-alkoxy-benzyl-oxopyrimidines （DABOs）, a class of highly potent non-nucleoside reverse transcriptase inhibitors （NNRTIs）, was studied by molecular docking followed by comparative molecular field analysis （CoMFA） and comparative molecular similarity index analysis （CoMSIA）. The results showed that the H-bonding interactions between the C=O and NH of the pyrimidine ring and Lys101, hydrophobic interactions between R, R1, X sites of ligands and neighboring amino acid residuals, and the electrostatic interactions between ligands and His235 and Lys101 residues were the dominant factors affecting the binding affinities. Based on an optimal docking conformation, 3D-QSAR models of 46 DABO derivatives were developed. The r^2 and cross-validated r^2 （q^2） of an optimal CoMSIA model were 0.862 and 0.532, respectively. Based on the QSAR studies, 9 new compounds were designed by the method of LeapFrog. The binding energies and docking scores （GScore） of 9 new compounds were better than that of a template molecule with the highest observed activity. The results showed that the molecular designs of DABOs should be focused on the hydrophobic interactions with the bottom of the binding pocket as well as van der Waals interactions with the entrance of binding pocket.展开更多
For the first time we report quantitative structure activity relationship (QSAR) studies based on Kier-Hall Electrotopological State (E-State) Indices for Dihydroalkoxybenzyloxopyrimidines (DABO) derivatives acting as...For the first time we report quantitative structure activity relationship (QSAR) studies based on Kier-Hall Electrotopological State (E-State) Indices for Dihydroalkoxybenzyloxopyrimidines (DABO) derivatives acting as NNRTIs of HIV-1. A dataset of 74 compounds was compiled from published studies and randomly subdivided into training and test sets. To understand the pharmacophoric effect, Kier-Hall Electrotopological State descriptors namely SN1, SN3, SF, SAr, SS, SO, SNO2, SCl, SY (Y = S-alkyl and NH-alkyl), SX (X = Me) and biological activity were used as independent and dependent variable respectively. Statistical results were highly encouraging for the training set multiple linear regression [(MLR): r2 = 0.961, F = 100.41 and q2 = 0.926, neural networks (NN): r2 = 0.966, F = 115.594, degrees of freedom = 40 and k-nearest neighbour (k-NN): r2 = 0.770, q2 = 0.757, degrees of freedom = 40]. Results of validation using a test set showed the same trend as training set (NN > MLR > kNN). The above results suggest that of various functional groups present in DABO such as SN3, SO, SCl, SAr and SNO2 contribute more significantly towards activity. On the other hand SN1, SS, and SF do not play any role in enhancing the activity. The substitution of S-alkyl and NH-alkyl at C2 position is essential though it does not contribute much towards the activity. The substitution of methyl group at C5 position is unfavorable and exhibit negative impact on inhibitory activity. Therefore, it seems reasonable to choose E-state indices as suitable and significant descriptors for exploring the relationship between the pIC50 and the pharmacological properties of the compounds.展开更多
基金Supported by the Fundamental Research Funds for the Central Universities (No. CDJZR10230010)the Third Stage Training of 211 Project (No. S-09104)
文摘A series of 46 dihydro-alkoxy-benzyl-oxopyrimidines （DABOs）, a class of highly potent non-nucleoside reverse transcriptase inhibitors （NNRTIs）, was studied by molecular docking followed by comparative molecular field analysis （CoMFA） and comparative molecular similarity index analysis （CoMSIA）. The results showed that the H-bonding interactions between the C=O and NH of the pyrimidine ring and Lys101, hydrophobic interactions between R, R1, X sites of ligands and neighboring amino acid residuals, and the electrostatic interactions between ligands and His235 and Lys101 residues were the dominant factors affecting the binding affinities. Based on an optimal docking conformation, 3D-QSAR models of 46 DABO derivatives were developed. The r^2 and cross-validated r^2 （q^2） of an optimal CoMSIA model were 0.862 and 0.532, respectively. Based on the QSAR studies, 9 new compounds were designed by the method of LeapFrog. The binding energies and docking scores （GScore） of 9 new compounds were better than that of a template molecule with the highest observed activity. The results showed that the molecular designs of DABOs should be focused on the hydrophobic interactions with the bottom of the binding pocket as well as van der Waals interactions with the entrance of binding pocket.
文摘For the first time we report quantitative structure activity relationship (QSAR) studies based on Kier-Hall Electrotopological State (E-State) Indices for Dihydroalkoxybenzyloxopyrimidines (DABO) derivatives acting as NNRTIs of HIV-1. A dataset of 74 compounds was compiled from published studies and randomly subdivided into training and test sets. To understand the pharmacophoric effect, Kier-Hall Electrotopological State descriptors namely SN1, SN3, SF, SAr, SS, SO, SNO2, SCl, SY (Y = S-alkyl and NH-alkyl), SX (X = Me) and biological activity were used as independent and dependent variable respectively. Statistical results were highly encouraging for the training set multiple linear regression [(MLR): r2 = 0.961, F = 100.41 and q2 = 0.926, neural networks (NN): r2 = 0.966, F = 115.594, degrees of freedom = 40 and k-nearest neighbour (k-NN): r2 = 0.770, q2 = 0.757, degrees of freedom = 40]. Results of validation using a test set showed the same trend as training set (NN > MLR > kNN). The above results suggest that of various functional groups present in DABO such as SN3, SO, SCl, SAr and SNO2 contribute more significantly towards activity. On the other hand SN1, SS, and SF do not play any role in enhancing the activity. The substitution of S-alkyl and NH-alkyl at C2 position is essential though it does not contribute much towards the activity. The substitution of methyl group at C5 position is unfavorable and exhibit negative impact on inhibitory activity. Therefore, it seems reasonable to choose E-state indices as suitable and significant descriptors for exploring the relationship between the pIC50 and the pharmacological properties of the compounds.
