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2008, 9, 181-197
International Journal of
ISSN 1422-0067 © 2008 by MDPI www.mdpi.org/ijms/ Full Research Paper
Some QSAR Studies for a Group of Sulfonamide Schiff Base as Carbonic Anhydrase CA II Inhibitors
Erol Eroglu * Department of Physics, Faculty of Sciences and Arts, Harran University, Osmanbey Campus, Sanliurfa 63300, Turkey. E-mail: email@example.com Received: 7 January 2008 / Accepted: 17 January 2008 / Published: 26 February 2008
Abstract: In the present study, quantitative structure–activity-relationship (QSAR) study on a group of sulfonamide Schiff-base inhibitors of Carbonic Anhydrase (CA) enzyme has been carried out using Codessa Pro methodology and software. Linear regression QSAR models of the biological activity (Ki) of 38 inhibitors of carbonic anhydrase CA-II isozyme were established with 12 different molecular descriptors which were selected from more than hundreds of geometrical, topological, quantum-mechanical, and electronic types of descriptors and calculated using Codessa Pro software. Among the models presented in this study, statistically the most significant one is a five-parameter equation with correlation coefficient, R2 values of ca. 0.840, and the cross-validated correlation coefficient, R2 values of ca. 0.777. The obtained models allowed us to reveal some physicochemical and structural factors, which are strongly correlated with the biological activity of the compounds. Keywords: schiff base sulfonamide; QSAR; Carbonic Anhydrase CA.
1. Introduction The metallo-protein carbonic anhydrase (CA, EC 22.214.171.124) is one of the most widely spread biological catalysts all over the phylogenetic tree. In humans, isozymes I, II, and IV are involved in respiration and regulation of the acid/base homeostasis. These complex processes involve both the transport of CO2/bicarbonate between metabolizing tissues and excretion sites (lungs, kidneys), facilitate CO2 elimination in capillaries and pulmonary microvasculature, eliminate H+ ions in the renal tubules and collecting ducts, as well as help in the reabsorption of bicarbonate in the brush border and thick ascending Henle loop of the kidneys. By producing the bicarbonate-rich aqueous humor secretion (mediated by ciliary processes isozymes CA I, II, CA IV and CA XII) within the eye, CAs
To the best of our knowledge.Int. Quantitative structure activity relationship (QSAR) studies are tools for predicting endpoints of interest in organic molecules acting as drugs . CA II is also involved in the bone development and in functions such as the differentiation of osteoclasts or the provision of acid for bone resorption in osteoclasts [1-4]. it will demonstrate as to which descriptors have bad or missing values. we investigated QSAR for 38 sulfanilamide Schiff’s base inhibitors of the physiologically relevant isozyme CAII using Codessa Pro approach . initial geometry optimizations were carried out with the molecular mechanics (MM) method. or can derive several best regression models. All the computations were carried out for the ground states of these molecules as single states. Computational details For all the molecules studied. The results of this study may help estimate the inhibition activity of sulfonamide with Schiff base of this series. The lowest energy conformations of the molecules obtained by the MM method were further optimized by the DFT  method by employing Becke’s three-parameter hybrid functional (B3LYP)  and the 6-31G (d) basis set. and thermo dynamical descriptors were involved in the obtained models presented in the following section. and their misfunctioning leads to high intraocular pressure and glaucoma. 2008. The majority of molecules in our set have been newly synthesized and till now they have not been conducted in any QSAR study.1. Results and Discussion 2. Many physiological activities of a molecule can be related to their composition and structure. HM can either quickly give a good estimation about what quality of correlation to expect from the data. Mol. 2. there have been a number of QSAR studies of sulfonamides using quantum chemical [7-14] and topological [15-24] descriptors and 3-D approach of CoMFA and CoMSIA . 9 182 are involved in vision. are used for performing QSAR analysis . Sulfonamides represent the most important class of biologically active compounds as inhibitors of CAs. It is worthy to mention here that we used a high level of theory (DFT/B3LYP) to obtain more precise data of descriptors during the calculation of the optimized 3-D geometry and quantum mechanical descriptors of the compounds. Sci. In this study. This code uses diverse statistical structure property/activity correlation techniques for the analysis of experimental data in combination with the calculated molecular descriptors. although no geometric. which are numerical representations of the molecular structures. Codessa Pro was used for statistical analysis. 3-D modeling and calculations of quantum mechanical descriptors were performed using the Gaussian 03 quantum chemistry package . The presence of these isozymes in so many tissues and in a number of different isoforms represents an attractive objective for the design of inhibitors with biomedical applications. J. In the literature. The heuristic method (HM)  implemented in Codessa Pro was employed for selecting the ‘best’ regression model. using the MM+ force fields. To save computational time. which descriptors are insignificant. Their fundamental vibrations were also calculated using the same method to check if there were true minima. and which descriptors are . prior to synthesis. quantum mechanical. 10] have been carried out using sulfonamides with Schiff base as Carbonic anhydrase inhibitors. Molecular descriptors. Besides. To the best of our knowledge. all QSAR studies using sulfonamides with Schiff base have been performed on the same data set. four QSAR studies [26-28.
Int. 2008. the cross-validated. the following criteria are applied and a descriptor is eliminated if: (a) the F-test’s value for the one-parameter correlation with the descriptor is below 1. Using the HM. and five parameters) were selected as models and are given in Table 2. These two parameters were calculated using WEB tool of ALOGPS 2. Among the regression results. five equations (the best one. logarithm of 1-octonal/water partition coefficient (logP) and logarithm of aqueous solubility (logS) to the descriptor pool. 9 183 highly inter-correlated. A stepwise addition of further descriptor scales is performed to find the best multi-parameter regression models with optimum values of statistical criteria (highest values of R2. Sci. This information will be helpful in reducing the number of descriptors involved in the search for the best QSAR model. two. Mol.1 by default and t1 1.1 software . A pre-selection of descriptors is accomplished by HM as follows. with another descriptor. A printout showing descriptors thus discarded is provided. is a measure of the fit of the regression equation.2. All the remaining descriptors are then listed in the decreasing order according to the correlation coefficient of the corresponding oneparameter correlation equation. the correlation coefficient. Thereafter. (c) the parameter’s t-value is less than t1 (where R2 min 0. the Fisher test value. The experimental inhibitory activity of the compounds against CA II isozyme was taken from three references [35-37]. The calculation results of the properties are listed in the WEB for each software and in the average of six softwares as well. All descriptors are checked to ensure that (a) value of each descriptor is available for every structure and (b) there is a variation in these values. Higher values of F-test indicate the significance of the equation. and the F value). R2. and (d) the descriptor is highly inter-correlated (above rfull. the one-parameter correlation equations for each descriptor are calculated. LOO approach involves developing a number of models. The inter-correlation of descriptors is shown in Table 3. F. (b) the squared correlation coefficient of the one-parameter equation is less than R2 min 0. with one sample omitted at . R2CV. The plot of observed versus calculated Ki for CA II using model 5 is shown in Figure 2. and (iii) the calculated Ki (nM) values using the best model 5 obtained in this study. four.1. s2 is the standard deviation of the regression. the ‘leave one out’ (LOO) cross-validated coefficient. In these models. R2 CV. The descriptors for which values are not available for every structure in the data in question are discarded. All two parameter regression models with remaining descriptors are developed and ranked by the regression correlation coefficient R2.0. 2. we have also added two physicochemical properties of compounds. namely.5 by default are user-defined values). three. In addition to the descriptors calculated using Gaussian 03 and Codessa Pro. To further reduce the number in the ‘‘starting set’’ of descriptors. reflects the ratio of the variance explained by the model and the variance due to the error in the model.01 by default. Results The structures of 38 Schiff-base sulfonamide compounds are shown in Figure 1. where rfull is a user-specified value by default 0.80). J. Descriptors having a constant value for all structures in the data set are also discarded. is a practical and reliable method for testing the predictive performance and stability of a regression model. (ii) experimental Ki (nM) values taken from the original references. This WEB tool calculates logP and logS using six different softwares and algorithms including ALOGPS 2. Table 1 shows the following information: (i) calculated molecular descriptor values involved in the models. several regression equations were obtained in this study. We have used average values of logP and logS from six different softwares in the regression procedures.
the author has constructed some common quantum chemical indices. four and five parameter equations were increased dramatically such as statistical parameters for five parameter equation R2 from 0. After selecting these two compounds as outliers.71 to 0. In this way. This result indicates that inhibition mechanism of Schiff-base sulfonamides is different from that of the aromatic and heterocyclic sulfonamides. Thermodynamic descriptors are quantum mechanically calculated on the basis of the total partition function of the molecule Q and its electronic. and the degree of branching of a molecule. Mol. It is ^ . electronegativity. descriptors are divided into groups such as constitutional. electrostatic. topological. geometrical. translational. two. encoding information about the size. Codessa Pro also allows one to construct new descriptors by using the existing descriptors. shadow indices. Geometrical descriptors are calculated from 3-D atomic coordinates of the molecule and comprise moments of inertia. namely. When the heuristic method has been run with default for 38 compounds. and y î the predicted activity of compound i computed by the new regression equation obtained each time after leaving out one datum point (No. compounds 29 and 38 have had the largest standard residual (almost twice of mean residua). chemical hardness. The correlation coefficient was very poor. less than (R< 0. Topological descriptors include valence and non valence molecular connectivity indices calculated from the hydrogen-suppressed formula of the molecule. For comparison. the best one. In our previous studies [13-14]. F from 15. quantum chemical. which is attributed to the fact that no quantum chemical indices has turned out in our models. and constructed.54. After developing each model.061 to 0. molecular surface areas. three. In all these five equations. The R2CV values are then calculated according to the following formula : 2 = 1− RCV ^ ⎛ ⎞ − y y ⎜ i ∑ î ⎟ ⎠ i =1 ⎝ _ ⎛ ⎞ − y y ⎜ ∑ i i ⎟ ⎠ î =1 ⎝ n − n 2 2 where yi is the actual experimental activity. Electrostatic descriptors reflect characteristics of the charge distribution of the molecule. the QSAR models have been drawn up from the quantum mechanical descriptors of a group of diverse aromatic and heterocyclic sulfonamides and from the inhibitory activity of these compounds against CA II isozyme. more than two hundred descriptors were exploited. Sci. Quantum chemical descriptors encode the polar interactions between molecules or their chemical reactivity and the activation energy of the corresponding chemical reaction. the statistical quality of one. four and five parameter equations have shown up as the program output. composition. these two compounds exhibited unusual behaviors in all the models. and electrophilicity from HOMO and LUMO orbital energies.96 to 31. y i the average actual experimental activity. and s2 from 0. In the present work. In Codessa Pro.034. and vibrational components. i). Constitutional descriptors are related to the number of atoms and bonds in each molecule. rotational. molecular volumes. 9 184 a time. two. the omitted data are predicted and the differences between the experimental and predicted activity values are calculated. and gravitation indices. we have tried to correlate inhibitory activity KiCA II of molecule set of this study (Schiff base sulfonamides) with the same quantum mechanical descriptors involved in QSAR models in our previous works. 2008.1). thermodynamic. The results shown in Table 2 have been quite surprising. three.84.Int. According to the preliminary regression analysis. J.
When models 1 and 2 are considered together. These two descriptors are constitutional.729. The negative sign of coefficient of DPSA-1 highlights a decrease in the magnitude of RNDB.245 + 1. F=28.16. In the above equation. 2008. statistically the best one is as follows: LogCA II-Ki= 6. The use of HM method yielded the best one-parameter regression expression as follows.618. In this model. which favors the exhibitions of the inhibitory activity of CA II-Ki. Mol. According to the models. two. as well as the models presented below.Int.599. RNDB is the relative number of double bonds. R2 CV = 0.090 (1) Here and thereafter. RNDB is a constitutional descriptor and has a coefficient with a negative sign. NBR is the number of benzene rings and NCA is the number of C atoms in the molecules. s2=0. F=37. three. RNBR has a positive-sign coefficient. Among the obtained two-parameter models. RNBR is the relative number of benzene rings. statistically the best one is as below: LogCA II-Ki= 1. LogCA II-Ki= 0.296 NBR – 0. 9 185 worthy here mention that the descriptors involved in the best equations obtained for 38 compounds set and 36 compounds set are not the same. .0031 DPSA-1 + 24. both models highlight the same features of the molecules. R2 CV is the ‘leave one out’ (LOO) cross-validated coefficient.055. The best one. R2=0. This means that increases in the magnitude of RNBR favors the exhibitions of the inhibitory activity of CA II-Ki.527. RNBR is the ratio between the numbers of benzene rings divided by the total number of atoms in the molecules. MiPCN is an electrostatic descriptor and reflects minimum partial charge on the N atom in the molecules. s2 = 0. substituting benzene with nitro or hydroxy groups instead of methyl groups and decreasing the number of CH2 bond to imine nitrogen are favorable for an increase in the inhibition activity of the compounds. R2 CV=0. Sci. F is the Fisher-statistic value.182 . A perusal of Table 2 shows that twelve types of descriptors are involved in all the five models. A decrease in the magnitude of RNDB favors the exhibitions of the inhibitory activity of CA II-Ki. N is the number of compounds. DPSA-1 is defined as the difference in CPSAs (PPSA1 (partial positive surface area) -PNSA1 (partial negative surface area)) [Zefirov's PC] and MiPCN is the Min partial charge for a N atom [Zefirov's PC].647. four and five parameter equations obtained from 36 compounds are presented as models in following.267MiPCN N=36.767 RNBR N=126.96.36.199 + 32. F = 30. DPSA-1 is an electrostatically charged partial surface-area descriptor and encodes features responsible for polar interactions between molecules. and s2 is the standard deviation of the regression equation.74.119 NCA N = 36. Among the obtained three-parameter models.069 (2) In this model. NBR has a coefficient with positive sign and NCA has a coefficient with a negative sign.733 RNDB – 0. s2=0. In this model. R2 is the correlation coefficient. J.488. R2 = 0. The positive sign of the coefficient of MiPCN indicates that increases in the magnitude of MiPCN are favorable for an increase of inhibition activity of the compounds. (3) In this model. R2=0. compounds 29 and 38 are outliers. R2 CV=0.
RPCG. The positive sign of coefficient of ALP indicates that Log CA II-Ki increases with increase in the magnitude of Average logP.and seven-parameter equations were greater than those of equation 5.777. HM uses maximum five descriptors to construct a regression model. 9 Among the obtained four-parameter models. This has yielded several six. NNA the Number of N atoms.279 NCA + 0. 3χ is the Randic index (order 3). This model is as shown below: LogCA II-Ki= -2. average logS. We have changed the default setting of the software in order to allow for the use of more than five descriptors. and describes the atomic connectivity and branching information of the molecules.Int. The positive sign of coefficient of 2AIC indicates that increases in the magnitude of 2AIC are favorable for an increase of inhibition activity of the compounds.122 RNDB + 7. J. 2008. Discussion Twelve types of descriptors were involved in the models. R2=0.577 RPCG N=36. namely. the RPCG Relative positive charge (QMPOS/QTPLUS) is an electrostatic descriptor.205 + 1. average . ALP is the logarithm of 1-octonal/water partition coefficient and exhibits hydrophobicity of compounds. ALP the Average logP.977 2AIC N=36.061 – 0. RPCG is the Relative positive charge (QMPOS/QTPLUS) [Zefirov's PC]. None of those equations has better statistic parameters than the above five parameters (equation 5).9. 186 (4) In this model. and reflects characteristics of the charge distribution of the molecules.462 ALS – 0. the sign of coefficients of NBR and NCA is the same as in that in the model 2 and thus they carry the same significance as in that model. and RNDB is the relative number of double bonds as in model 4. statistically the best one is as shown below: LogCA II-Ki= 1. 2AIC is the second-order average complementary information content that could be considered an index of heterogeneity of a molecule . The negative sign of the coefficient of ALS highlights a decrease in the magnitude of ALS.034. equation 5 consisting of NBR the Number of benzene rings. we obtained several five-parameter equations. s2=0. ALS.716. and ALP. average logP. 3χ is a topological descriptor.282 ALP + 0. This means that the increase in the magnitude of NNA is the favorable parameter for the exhibition of the inhibitory activity.54. During our regression analysis using HM. In model 4. F=31. Mol. Two of the descriptors are physicochemical property. 2.48. R2 CV=0. ALS is the Average LogS. This means that the third-order branching is not the favorable parameter for the exhibition of the inhibitory activity. s2=0.182 NNA + 0. Sci.3.840.739 NBR – 0. R2 CV=0. NNA is a constitutional descriptor. F=28. and 2AIC the Average information content (order 2) is the best.and seven-parameter regression equations.125 3χ . they were not selected as models in this study due to their relatively low F value. which favors the exhibitions of inhibitory activity of CA II-Ki. 3χ has a coefficient with a negative sign. Out of these five-parameter equations. NCA the Number of C atoms.786. R2=0. (5) In this model. Although R2 values of those six.045. It has a positive sign of coefficient. The positive sign of the coefficient of RPCG indicates that increases in the magnitude of relative positive charge of molecules are favorable for an increase of the inhibition activity of the compounds. ALS is the logarithm of aqueous solubility of the compounds. By default setting.
negatively contribute to the inhibitory activity in the models 2 and 3. one could draw a conclusion that one should avoid substituting benzene rings with C-containing groups and adding CH2 bond to imine nitrogen for designing Schiff-base sulfonamide compounds with increased inhibitory activity. Five of the involved descriptors are constitutional. the number of C atoms.Int. J. 9 187 logS negatively contribute to the inhibitory activity. When these two results are combined together. average logP positively contributes to the inhibitory activity. the number of N atoms which positively contribute to the inhibitory activity in model 5. and NBR. Sci. RNBR. Mol. H2NO2S O SO2NH2 N ( )n R O O N O N SO2NH2 R H2NO2S (CH2)n N R O H C R3 R1 R2 N 1 2 3 4 5 6 R=H n=0 R=H n=1 R=H n=2 R=Me n=0 R=Me n=1 R=Me n=2 O 7 R=H 8 R=Me N NH 9 R=H F3C 10 R=Me SO2NH2 R4 A= H2NO2S (CH2)n N CHR N Me Compound 22 23 24 25 n 0 0 1 2 R PhCH=CHA B B B= N Me N OH 32 N SO2NH2 Compound 11 12 13 14 15 16 17 18 19 20 21 26 27 28 29 30 31 33 34 35 36 37 38 n 0 0 1 1 1 1 1 1 2 2 2 0 0 0 0 0 0 1 1 1 2 2 2 R1 Cl OMe Cl H H NO2 H H Cl H NO2 H H H H H H H H H OH H H R2 H H H H H H H OMe H H H H Cl OMe H H H H H NO2 H H H R3 R4 H H H H H H OMe H AcNH H H H H NO2 OMe OMe H H AcNH H H H H OMe H H AcO H H NO2 Cl H OH H OH H AcNH H H H H H H H H NO2 Figure 1. the number of benzene rings in the models 2 and 5 positively contribute to the inhibitory activity. 2008. Molecular structure of Schiff-base sulfonamides used in the present study This result is expected due to the fact that the average logP is inversely proportional to the average logS. substituting benzene ring with nitro . Another constitutional descriptor is NNA. As a consequence. the relative number of benzene rings in model 1. On the contrary. NCA. In model 5.
3χ is the thirdorder Randic index which negatively contributes to the inhibitory activity in model 4. five-parameter equation consists of the descriptors namely the Number of benzene rings. it should be considered that the third-order branching is not the favorable parameter. and they characterize the charge distribution of the molecules. 9 188 groups or inserting an N-containing ring to a Schiff-base sulfonamide compound may help increase the inhibitory activity. Description Plot of observed versus predicted LogKi CA II values using model 5. positively contribute to the inhibitory activity in models 3 and 4.1E-05 R = 0. 2. 3χ and 2AIC. The values of these electrostatic indexes of molecules are affected by substituting groups.4. Another topological index is 2AIC.84. This means that if one wants to design a Schiff-base sulfonamide with high inhibitory activity. This descriptor reflects the heterogeneity of a molecule and positively contributes to the inhibitory activity in model 5. negatively contributes to the inhibitory activity in model 3. DPSA-1.8402 Observed LogKi (C A II) 2 2 1. Remaining three descriptors are electrostatic index.034. J. respectively.5 1 1 1. F= 31.5 y = x . the structural descriptors of 36 sulfonamide Schiff-base inhibitors of Carbonic Anhydrase CA II enzyme have been correlated with the their inhibition constant Ki using Codessa Pro methodology. MiPCN. and RPCG Relative positive charge (QMPOS/QTPLUS) [Zefirov's PC]. Two descriptors. the Number of N atoms. 2008. Min partial charge for a N atom [Zefirov's PC]. The statistical parameters of this model are the R2 = 0. Difference in CPSAs (PPSA1-PNSA1) [Zefirov's PC]. and s2 = 0. the Average logP. R2 CV=0.54.77.5 Predicted LogKi (CA II) 2 2. and the Average information content (order 2) is the best one. out of twelve are topological index. . Conclusion In the present study. Sci.5 Figure 2. Among the obtained model. the second-order average information content. Mol. the Number of C atoms.Int. 2. This should be taken into account when one tries to design a new molecule.
3330 6.0000 14.0465 0.7700 2.544 1.3122 8.9300 -5.3724 2.3815 2.1064 ALS -4.518 1.0004 -0.000b 1.0956 -0.9000 2.8494 6.5200 -2.0000 20.0000 2. J.0000 3.0000 18.9000 -4.1250 0.0000 2.0932 -0.3376 -0.698 b b b 1.0000 13.0701 20.0488 0.041 2.0000 14.008 a a a 2.146 1.9900 -4.2996 6.1351 0.1682 4.1125 0.8359 117. Ki 1.1070 NNA 2.4000 -3.0857 Residue 0.0000 5.0830 7.3200 -4.1800 2.0833 0.0600 -4.0303 NBR 2.0000 12.1145 0.2600 1.0000 2.0000 2.0000 2.0417 0.0909 0.4900 1.1474 0.0000 2.0000 3.8479 -22.1153 0.0865 0.0000 1.1200 3 189 χ RPCG 0.6900 -0.9578 1.4996 1.0000 2.0000 3.8093 165.0000 2.461 2.0000 21.1015 -0.3173 7.0000 5.0606 0.0732 0.0000 2.0000 2.0000 3.230 1.6547 8.0912 -0.1338 0.0980 -0.0652 0.0336 0.0811 0.7556 4.9300 1.0436 3.0900 -4.0000 2.7243 1.1250 0.3417 65.9603 122.8666 2.0444 0.0000 3.0000 15.0435 0.0099 105. Calculated descriptors involved in the models and LogCA II-Ki of 38 sulfonamides compounds predicted by model 5.2979 4.0500 0.6421 291.6494 1.2531 4.1462 10.0906 0.0000 17.0465 0.3100 -4.7979 7.1100 -3.4512 4.2087 0.9908 4.1797 -0.0980 -0.0000 2.5507 1.0000 15.1002 -0.2710 6.0912 -0. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 RNBR 0.6000 1.1147 -0.418 0.4434 4.0374 -0.954 2.8184 113.3951 4.9700 1.0000 2.0000 3.0000 2.4600 -4.301 b b b b b b b b 2.2916 1.3549 1.0855 0.8331 1.1193 0.0934 0.3855 4.123a 2.0004 1.8900 1.6557 1.0541 0.4600 -5.3900 -3.0967 -0.1001 -0.1744 -0.0000 3.0000 2.740 a a a 1.0000 1.7700 -2.1087 0.6100 2.7782 54.1300 -4.3900 1.3033 0.0488 0.6400 2.0556 0.9864 3.447 a Pre.1267 0.2153 8.0872 -0.0000 16.4747 1.1556 0.0000 2.8300 1.1043 -0.0000 2.0000 2.1040 0.0857 0.1163 0.322b 1.1043 -0.1305 8.0967 -0.1143 0.6325 138.301 b . 9 Table 1.0955 0.0902 0.0000 3.1803 -0.778a 1.397 1.0000 15. Ki 1.6081 6.1458 0.1367 0.079 2.0500 0.0000 15.1794 111.5070 10.0000 17.0828 0.8703 11.0789 0. 2008.2719 3.1287 0.5479 6.3006 4.0323 0.0000 2.0999 -0.3900 1.0886 -0.0000 2.0000 12.0000 NCA 16.8038 8.5054 -18.0000 2.0986 -0.0984 -0.1169 0.0894 0.0600 2.1247 2.1351 0.8128 2.0000 2.8300 1.6600 1.0588 0.3063 6.1250 0.0900 -111.0000 19.0085 -0.0950 0.322 1.0454 -0.0526 0.0000 ALP 1.7736 3.0673 7.0000 2.6266 90.1893 -0.1001 -0.6333 1.0539 4.1082 0.0019 140.0000 18.1504 0.0571 0. Comp.1176 DPSA-1 21.0000 3.6593 130.0000 17.3257 1.0000 2.0675 0.0231 59.8962 9.Int.0991 -0.1042 0.0154 2.1400 -4.8272 MiPCN -0.6356 4.0935 -0.5694 4.1163 0.0600 -3.8192 4.8380 40.0444 0.0980 0.9995 2.0667 0.1579 4.0000 2.0882 0.0000 2.9200 -4.9000 2.7607 -67.0000 2.2556 2.4600 2.1241 0.7700 -4.1000 -0.0000 14.4700 1.2632 1.0000 17.0571 0.1776 0.4307 4.1144 4.9476 3.0526 0.4428 68.0872 -0. Mol.0000 2.1212 -0. Sci.2600 -3.5640 1.9535 4.1053 0.146a 1.5538 8.0000 14.2127 10.0968 0.0693 0.0455 0.602 2.6297 3.0000 2.612 2.3000 2 AIC Obs.0000 2.0588 0.7900 -4.2884 1.8399 7.6019 31.0976 0.0833 0.0693 0.2108 -0.0000 4.8000 -4.0000 2.0000 RNDB 0.0563 6.0800 2.477 2.0000 18.9200 -3.0571 0.5200 0.0000 17.1076 -0.0000 2.8476 155.
RPCG.301 c RNBR. d) Compounds 29 and 38 are outliers and were deleted from the regression procedure of model 5.1570 186.8615 61.0600 2.0000 2.0000 2.0941 -0.0000 2.0909 0.0000 2.0000 2. NNA.0000 13.0278 0.0857 0. NBR.4402 2.000b 2.0000 3.0997 -0.3700 -3.255 2.602 c c c 1. Number of C atoms .1037 43.0932 -0.1224 0.1901 6.2710 7.0833 0. ALP.0000 2. 3χ.0000 13.0993 0.5479 6.3500 -2.7736 4.0789 0.2300 1.8565 4.0889 2.1629 -0.0950 0.0000 2.8927 -5.0556 0.1013 -2.230 2. Min partial charge for a N atom [Zefirov's PC].1081 0.1064 -0.5748 32.698c 2.3929 3.8082 8.0000 0.1751 0.3063 6.4317 7.0000 13.1267 0.6366 -0.0000 14. .0968 0.0000 15.2709 -- 1. RNDB.1103 4.0500 0.8000 -4.000 c c c 0.0000 3.8889 6.1652 0.0946 -0.146c 1.0273 -0.2700 -3.1498 0.1294 0.0000 2.1015 0.8939 -2.0645 0. Average logS.0625 0.1029 1.1829 0.0541 0.8400 2.8082 -22.0000 2. NCA.4500 1.7672 2.3600 -3.1202 1. Mol.1427 1.1001 -0.1001 -0.1429 0.8581 2.0000 2.2500 -4.0000 2.1432 0.0673 7.0000 13.8574 3. ALS.0526 1.0000 2.1785 0.1200 1. Relative number of double bonds.0000 2.3200 2.447 2.0968 0.0000 2.7829 -23.0000 2.4823 3.7069 3. Randic index (order 3). Number of N atoms.0000 2.0000 16. c) From Ref.0000 13. Relative number of benzene rings. and 2AIC.1901 3.1852 0. Average logP.3700 0.0811 0.9698 4.278 1.2531 4.0667 0.0934 -0.0476 0.7929 3.6262 112.0000 15. b) From Ref. Average Information content (order 2) a) From Ref.845c 2. . Number of benzene rings.5000 2.1824 3.0000 0.4766 -51.1241 0.3600 -3.0000 7.7851 135.1061 --0.3805 0. 9 25 26 27 28 29d 30 31 32 33 34 35 36 37 38 d 190 1.1143 -0.0000 3.0946 -0.7274 112.0000 14.0000 13.2600 -4.0000 1.0500 -4.0000 2.0000 3.1007 4.3063 7.1017 -0.1100 -3.0976 0.041 2.0497 -0. .0000 16.0938 0.1511 0.0072 -0.0624 6. J.4100 1.0500 0.0000 2. 2008.1350 0.0726 -0.7979 6.0571 0. DPSA-1 Difference in CPSAs (PPSA1-PNSA1) [Zefirov's PC].1164 0.8125 3.0645 0.0769 209.Int.0000 15.113 c c c 2.0000 2.7600 2. Sci.0976 0.0497 2.6400 1. RPCG Relative positive charge (QMPOS/QTPLUS) [Zefirov's PC].5542 6.7200 -4.5200 1.1002 -0.8751 -- 0.1900 6.0000 2.3894 1.6016 6.0000 2.7257 3.2027 2.462 2. .2200 4. MiPCN.1900 -4.3327 2.0588 0.4800 1.0938 0.0947 -0.0667 0.0079 1.2300 -3.0749 -0.
527 0. 9 191 Table 2.647 0.618 28.462(0.122(2.170) -0. Regression parameters and statistical quality of the correlations of the activity LogKi -CAII in the present study.739(0.74 0.5) Equ. 1 Equ.54 0.078) -0.786 0.458 3.055 1.930) 1.061 (0.98 30.280) 0.0031(0.716 29.609 3.127) -0.020) 7.282(0.119(0. J.977(0.777 31. 2008.045 χ Randic index (order 3) RNDB Relative number of double bonds RPCG Relative positive charge (QMPOS/QTPLUS) [Zefirov's PC] Equ.020) -16.940) 36 0.73(2.98 0.245 (0.069 6.826 -7.488 32.887 -2.2.0005) 24.090 0. 4 ALS Average logS 3 B (intercept) 0.296(0. 5 NBR Number of benzene rings NCA Number of C atoms NNA Number of N atoms ALP Average logP 2 -2.767(5.316) 1.4.078) 0.180 (0.034 AIC Average Information content (order 2) .3.205 (0.Int.729 0.037) 0. Models Descriptors involved t-test Coefficient Ai (i=1.488 0.578 3.163 7.330) 36 0.590 -5.939 -5.051) 0.27 0. 3 RNDB Relative number of double bonds DPSA-1 Difference in CPSAs (PPSA1-PNSA1) [Zefirov's PC] MiPCN Minimum partial charge for a N atom [Zefirov's PC] Equ.745 -7.279(0.125(0.298) 6.571 -4. Mol.182 (0. Sci.924 7.510 3.107) -0.222) -0. 2 RNBR Relative number of benzene rings NBR Number of benzene rings NCA Number of C atoms Equ.406 -5.515 3.577(1.182(0.840 0.276(7.280) 1.599 37.048) -9.776) 36 36 36 Statistical Parameters N R2 R2 cv F s2 0.
3χ.3227 0.6935 1.5991 -0.0431 -0.4810 0. Average logS.6504 -0.3227 1.000 -0.1964 -0.4068 -0. Average Information content (order 2).4310 0.2939 0. Average logP.2953 0.1693 -0.Int.7380 1.6106 -0.4510 0. Correlation matrix for the inter-correlation of various molecular descriptors involved in the obtained models. MiPCN.2953 0.000 0.0203 NCA RNDB DPSA-1 MiPCN ALS 3 χ RPCG NNA ALP 2 AIC 1.1773 0.5260 0. NCA.1964 0. ALP. Relative number of double bonds.0882 -0.4134 -0.3609 0.3454 -0.3333 0.2939 0.7793 -0.7565 0.7380 0.4294 0.000 -0. RNBR RNBR NBR NCA RNDB DPSA-1 MiPCN ALS 3 NBR 1. Min partial charge for a N atom [Zefirov's PC]. Sci.3372 -0.0307 -0. 9 192 Table 3. .7013 0.7649 -0.3372 -0.1979 -0.5658 1. Number of C atoms .000 -0.2483 -0.3005 0.000 -0.3141 -0. DPSA-1 Difference in CPSAs (PPSA1-PNSA1) [Zefirov's PC]. 2008.5991 0. ALS.000 -0.3573 -0.000 -0. J.000 -0.2031 -0. Relative number of benzene rings.2484 -0.2484 1.4079 0. RPCG Relative positive charge (QMPOS/QTPLUS) [Zefirov's PC].000 -0.2031 -0.2244 -0.3572 1.6106 0. NBR.7993 1. Randic index (order 3). Mol.000 χ RPCG NNA ALP 2 AIC RNBR.0337 0.2802 1.000 0. NNA.6935 -0.4134 0.0203 0.1155 1. and 2AIC. RNDB.2183 0.7793 0.3005 0.3105 0.5717 -0.000 0.4106 -0.2007 -0. Number of N atoms.6052 1. Number of benzene rings.
The average information content is defined on the basis of the Shannon information theory and is calculated as follows [42-43]: n n k IC = −∑ i log 2 i n i n where ni is a number of atoms in the i-th class and n is a total number of atoms in the molecule. Randic and Kier & Hall indices (order 0-3). These two indices are defined using the formula given below according to Codessa Pro reference Manual . Topological indexes Two topological indexes were involved in our models. Electrostatic indexes According to Codessa Pro reference Manual .. .Int. CIC – complementary IC.. Other information content indices (SIC – structural IC. Mol. Z iυ is the number of valence electrons. The general formula for the calculation of these indexes is as follows: n χ= i1. This leads to the indices of different order k. electrostatic indexes were involved in our models and are calculated using the formulae given below. and BIC – bonding IC) are defined as follows : k SIC = k IC / log 2 n k CIC = log 2 n− k IC k BIC = k IC / log 2 q where q is a number of edges in the structural graph of the molecule. in +1 ( paths − of −length − n ) ∑ (δ N SB δ )−1 / 2 where δ i and δ j ( i ≠ j ) correspond to the coordination numbers of atoms (Randic index ) or to the values of the atomic connectivity (valence connectivity index n χ υ by Kier and Hall ). The atomic connectivity for the i-th atom in the molecular skeleton is calculated using the formula: ( Z iυ − H i ) δi = ( Z i − Z iυ − 1) where Z i is the total number of electrons in the i-th atom. 9 3. The information content (IC) is equal to average information content multiplied by the total number of atoms. Sci. Information content index and its derivatives (order 0-2). 2008. and H i is the number of hydrogens directly attached to the i-th atom. The division of atoms into different classes depends upon the coordination sphere taken into account. Experimental Section 193 Inhibition of CA II The inhibition value LogCA II-Ki was adopted from the references [35-37]. J.
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