Topological descriptors in drug design and modeling studies.
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Combinatorial Chemistry Techniques↗
Biomedical subjects
Kunal Roy
Publications and source records attributed to Kunal Roy.
Exploring selectivity requirements for COX-2 versus COX-1 binding of 3,4-diaryloxazolones using E-state index.
Considering the importance of developing selective COX-2 inhibitors, the present paper explores selectivity requirements for COX-2 versus COX-1 binding of 3,4-diaryloxazolones using electrotopological state (E-state) index. The study also shows the utility of E-state index in developing statistically acceptable model having direct physicochemical significance: electron density distribution of different atoms of the oxazolone ring and attached two phenyl rings are important for the selective binding with COX-2 over COX-1. Moreover, the use of indicator variable shows that presence of ortho R(1) substituent (except fluoro) on the N(3)-phenyl ring decreases COX-2 selectivity. Further, an amino substituent at R(2) position (i.e., sulfonamide compound) is favorable for increasing COX-2 selectivity when the R(3) position is unsubstituted.
Chemical Phenomena↗
QSAR study on the affinity of some arylpiperazines towards the 5-HT1A/alpha1-adrenergic receptor using the E-state index.
QSAR models represent the relationship of biological activity with either physicochemical parameters or structural indices. QSAR study was performed on some arylpiperazines as 5-HT(1A)/alpha(1)-adrenergic receptor antagonists using E-state indices to identify the pharmacophoric requirements. It was found that some of the atoms played important roles to both activities and some played important role in selectivity of compound to the 5-HT(1A) antagonistic activity. The presence of COONHPr group at the ortho-position of the phenyl ring might be disadvantageous and Br at meta-position might be conducive to the activity. COOPr at the ortho-position might be disfavored the adrenergic alpha(1)-antagonistic activity, thus increase the selectivity.
Adrenergic alpha-1 Receptor Antagonists↗
Comparative QSPR studies with molecular connectivity, molecular negentropy and TAU indices. Part I: molecular thermochemical properties of diverse functional acyclic compounds.
Molecular thermochemical properties (heats of formation and atomization) of diverse functional acyclic compounds have been correlated with TAU indices and the relations have been compared to those involving molecular negentropy and first order valence molecular connectivity indices to unravel the diagnostic feature of the TAU scheme and to explore the relative suitability of the scheme in describing physicochemical parameters. For both the properties it was found that TAU relations could satisfactorily explain the variances of the thermochemical parameters and the relations were comparable to those involving molecular negentropy and molecular connectivity. Moreover, specific contributions of functionality, branchedness, shape and size factors to the thermochemical properties could be found from the relations involving TAU parameters.
Algorithms↗
QSAR study on some p-arylthio cinnamides as antagonists of biochemical ICAM-1/LFA-1 interaction and ICAM-1/JY-8 cell adhesion in relation to anti-inflammatory activity.
In an attempt to find out the chemical and structural features of some p-arylthio cinnamides 1 as antagonists of biochemical ICAM-1/LFA-1 interaction as well as ICAM-1/JY-8 cell adhesion in relation to anti-inflammatory activity, QSAR study was performed. Steric effect on the arylthio ring and lipophilic substitutions at 2,3-positions, especially 2,3-disubstitution with Cl or CF(3) or both on cinnamides 1 were conducive to the activity, whereas simultaneous presence of methoxy group at arylthio ring and NCOCH(3) group at heterocyclic ring of cinnamides 1 were detrimental to activity in antagonism of biochemical ICAM-1/LFA-1 interaction. When inhibition of ICAM-1/JY-8 cell adhesion was considered, lipophilic substitution on ring B and simultaneous presence of CF(3) groups at 2 and 3 positions of the ring B were advantageous to antagonism. This QSAR study showed that B ring has played the most important role for both types of activities.
Anti-Inflammatory Agents, Non-Steroidal↗
Quantitative structure-activity relationship study on some azidopyridinyl neonicotinoid insecticides for their selective affinity towards the drosophila nicotinic receptor over mammalian alpha4beta2 receptor using electrotopological state atom index.
Neonicotinoids are the most important class of synthetic insecticides increasingly used in agriculture and veterinary medicine. Fundamental differences between the nicotinic acetylcholine receptors (nAChRs) of insects and mammals confer remarkable selectivity of the neonicotinoids at insect nAChR over mammalian nAChR. To identify pharmacophoric requirements of azidopyridinyl neonicotinoids for their efficacy and selectivity towards the insect nAChR over the mammalian one, quantitative structure-activity relationship (QSAR) study was performed using electrotopological state atom (ETSA) indices. This study clearly showed that nitroimines, nitromethylenes, and cyanoimines are more selective to Drosophila nAChR and safe for human being, whereas N-substituted imines have affinity to mammalian receptor. Pharmacophore mapping for both the activities was done.
Anabasine↗
QSAR modeling of anti-HIV activities of alkenyldiarylmethanes using topological and physicochemical descriptors.
Three series of anti-HIV data (reverse transcriptase inhibitory activity, cytopathicity data, and cytotoxicity data) of alkenyldiarylmethanes were modeled with physicochemical, topological and structural descriptors by multiple regression analysis using principal component factor analysis as the data pre-processing step. Molar refractivity was found to be a significant contributor in modeling all three data sets. Apart from this, partition coefficient, E-state index, valence connectivity and indicator parameters were important in modeling different activity series. The final relations were of moderate to good quality as evidenced from regression statistics (R2 values ranging 66-75%) and leave-one-out cross validation data (Q2 values ranging 54-70%).
Alkenes↗
QSAR of human factor Xa inhibitor N2-aroylanthranilamides using principal component factor analysis.
Quantitative structure-activity relationship (QSAR) study of human factor Xa inhibitor N2-aroylanthranilamides, recently reported by Yee et al. (J. Med. Chem., 43, 873-882), has been performed using principal component factor analysis as the preprocessing step. The study reveals that presence of electron-donating R2 substituent at the para position (with respect to the amide linkage) is conducive to the binding affinity, whereas a meta R2 substituent decreases the affinity. Again, electron-donating R1 substituents with less bulk and optimum hydrophilic-lipophilic balance (particularly, methyl and methoxy groups) favor the activity. The study further suggests that electron-withdrawing R3 substituents are detrimental for the activity, whereas bulkier R4 substituents (particularly NHSO2Me group) increase the activity.
Antithrombin III↗
QSAR with electrotopological state atom index: human factor Xa inhibitor N2-aroylanthranilamides.
Recently, N2-aroylanthranilamides have been reported as novel series of possible anticoagulant drug candidates and the two aryl rings (A and B) have been suggested to interact with S1 and S4 regions, respectively, of human factor Xa (hfXa). In the present effort, quantitative structure-activity relationship (QSAR) of the hfXa binding affinity of 32 N2-aroylanthranilamides have been attempted, in continuation of our previous report on the QSAR analysis of the data set using linear free energy related (LFER) model, with electrotopological state atom (ETSA) index (Kier and Hall, 1991, Adv. Drug Design., 22, 1-38), to explore the atoms/regions of the compounds that modulate the activity comparatively to the greater extent. The univariate and bivariate relations involving the ETSA values of different common atoms of the compounds show importance of the atom nos. 12, 3 and 17 (arbitrary numbering): B ring carbon bearing meta R2 substituents, C ring carbon bearing R4 substituent, and carbonyl oxygen of A ring amide linkage. The importance of atom 12 is suggested to be due to detrimental effects of meta R2 substituents (B ring) on the hfXa binding affinity, which may be owing to interference in the attainment of the proper orientation of the phenyl ring in the S4 site. Atom 3 signifies the impact of R4 substituents (central C ring) on the binding affinity. Again, atom 17 (carbonyl oxygen of A ring amide linkage) has been suggested to form hydrogen bonding with the NH group of the other amide linkage, producing a pseudo ring and thus stabilizing the structure. The relations were improved further using indicator and physicochemical variables and the present results are in good agreement with the previous findings of the Hansch analysis.
Antithrombin III↗
QSPR modeling of lipid-water partition coefficient by optimization of correlation weights of local graph invariants.
The optimization of correlation weights scheme was applied to model lipid-water partition coefficient (log P) of two sets of diverse functional aliphatic and aromatic compounds. In both cases, the optimized descriptors formulated based on the data of training sets generated statistically acceptable relations for the corresponding training sets, test sets, and combined sets. When the relations of log P values with the optimized molecular descriptors formulated based on the data of the training sets were used for calculation of log P values of the corresponding training sets, rpred2 values were found to be satisfactory (above 0.99) in both cases, which is indicative of the predictive potential of the scheme. The results indicate promising potential of the optimization of a correlation weights scheme in modeling studies.
Journal Article↗
QSTR with extended topochemical atom indices. 2. Fish toxicity of substituted benzenes.
Considering the importance of quantitative structure-toxicity relationship (QSTR) studies in the field of aquatic toxicology from the viewpoint of ecological safety assessment, fish toxicity of various benzene derivatives has been modeled by the multiple regression technique using recently introduced extended topochemical atom (ETA) indices. The toxicity data have also been modeled using other selected topological descriptors and physicochemical variables, and the best ETA model has been compared to the non-ETA ones. Principal component factor analysis was used as the data preprocessing step to reduce the dimensionality of the data matrix and identify the important variables that are devoid of collinearities. All-possible-subsets regression was also applied on the parameters to cross-check the variable selection for the best model. Multiple linear regression analyses show that the best non-ETA model involves 1chi, ALogP98, and LUMO (energy) as predictor variables and the quality of the relation is as follows: n = 92, Q2 = 0.718, Ra2 = 0.730, R2 = 0.738, R = 0.859, F = 82.8 (df 3, 88), s = 0.340. On the other hand, the best ETA model has the following quality: n = 92, Q2 = 0.865, Ra2 = 0.876, R2 = 0.885, R = 0.941, F = 92.6 (df 7, 84), s = 0.230. The ETA relations showed positive contributions of molecular bulk (size), chloro and hydroxy substitutions in the benzene ring, and the simultaneous presence of methyl and nitro substitutions to the toxicity. Further, the presence of fluoro and ether functionality, amino or nitro functionality in an otherwise unsubstituted ring, and nitro functionality that is ortho to a chloro substituent decreases toxicity. An attempt to use non-ETA descriptors along with ETA ones did not improve the quality in comparison to the best ETA model. Interestingly, the ETA model developed presently for the fish toxicity is better than the previously reported models on the same data set. Thus, it appears that ETA descriptors have significant potential in QSAR/QSPR/QSTR studies, which warrants extensive evaluation.
Journal Article↗
QSAR analyses of 3-(4-benzylpiperidin-1-yl)-N-phenylpropylamine derivatives as potent CCR5 antagonists.
CCR5 receptor binding affinity of a series of 3-(4-benzylpiperidin-1-yl)propylamine congeners was subjected to QSAR study using the linear free energy related (LFER) model of Hansch. Appropriate indicator variables encoding different group contributions and different physicochemical variables such as hydrophobicity (pi), electronic (Hammett sigma), and steric (molar refractivity, STERIMOL values) parameters of phenyl ring substituents of the compounds were used as predictor variables. The Hansch analysis explores the importance of the lipophilicity and electron-donating substituents for the binding affinity. However, this method could not give more insight into the structure-activity relationships because of the diverse molecular features in the data set. 3D-QSAR analyses of the same data set using Molecular Shape Analysis (MSA), Receptor Surface Analysis (RSA), and Molecular Field Analysis (MFA) techniques were also performed. The best model with acceptable statistical quality was derived from the MSA, which showed the importance of the relative negative charge (RNCG): substituents with a high RNCG value have more binding affinity than the unsubstituted piperidine and phenyl (R1 position) congeners. The relative negative charge surface area (RNCS) is detrimental (e.g. R2 = 3,4-Cl2) for the activity. An increase in the length of the molecule in the Z dimension (Lz) is conducive (e.g. R3 = sulfonylmorpholino), while an increase in the area of the molecular shadow in the XZ plane (Sxz) is detrimental (e.g. R1 = N-c-hexylmethyl-5-oxopyrrolidin-3-yl) for the binding affinity. The presence of a chiral center makes the molecule less active (e.g. R1 = N-methyl-5-oxopyrrolidin-3-yl). An increase in the van der Waals area, the molecular volume, and the difference between the volume of the individual molecule and the shape reference compound are conducive (e.g. R3 = (CH3)2NSO2-) for the binding affinity. Substituents with higher JursFPSA_2 values (fractional charged partial surface area) like the N-methylsulfonylpiperidin-4-yl (R1 position) group have better binding affinity than the substituents such as 4-chlorophenylamino (R1 position). Unsubstituted piperidines (R1 position) with less JursFNSA_1 values have lower binding affinity than the 4-chlorophenyl substituted compounds. The MFA derived equation shows interaction energies at different grid points, while the RSA model shows the importance of hydrophobicity and charge at different regions of the molecules. The models were validated through the leave-one-out, leave-15%-out, and leave-25%-out cross-validation techniques. The developed models were also subjected to a randomization test (99% confidence level). Although the MSA derived models had excellent statistical qualities both for the training as well as test sets, RSA and MFA results for the test sets are not comparable statistically with the MSA derived models.
Anti-HIV Agents↗
Effect of desogestrel on blood-lipid in relation to its biological activities.
Desogestrel (DG), a 19-nor progestin, is widely used in replacement therapy as a contraceptive steroidal hormone. Considering the importance of its partition coefficient parameter (log P = 5.68), a significant contributor to its action mechanism, interactions of the drug with blood-lipids had been investigated using phospholipid binding, fatty acid composition and peroxidation phenomena as the parameters under investigation to explain its pharmacodynamic behavior. From the present investigation, it was observed that lipid loss after incubation of whole blood with DG (80 ng/ml, effective contraceptive concentration in blood) for varying periods of time was accompanied with significant changes in fatty acid composition, which may be ascribed to binding affinity of DG with lipid constituents in blood that may have a role in the mediation of its therapeutic effect. Lipid peroxidation induction potential of DG has been quantitatively measured in the context of its toxicity. The results reveal that DG caused significant extent of lipid peroxidation. Ascorbic acid, an antioxidant, at equivalent human dose of 250 mg could significantly reduce DG-induced lipid peroxidation.
Animals↗
Mechanism of in vitro release kinetics of flurbiprofen loaded ethylcellulose micropellets.
Flurbiprofen loaded ethylcellulose micropellets with different drug loading were prepared by a quasi-emulsion solvent diffusion technique. Encapsulation parameters of micropellets such as actual drug loading, drug encapsulation efficiency (DEE) and loss of coating polymer (LCP) were determined. Actual drug loading was increased with the increased initial drug loading whereas encapsulation efficiency decreased with the increase of actual drug loading. In vitro drug release profiles of these micropellets were evaluated in distilled water (DW) and also in phosphate buffer solution (PBS) to indicate pH dependency release rates. All the batches of micropellets released about 35-59% in DW and 89-97% in PBS during the period of 8 h and the burst effect of about 50-75% in the first 1.5 h was seen only in PBS. The mechanism of release kinetics was evaluated by fitting the release data to the zero order, first order, Higuchi, Baker-Lonsdale and Peppas equations and also to the differential forms of zero order, first order and Higuchi model. Adequate fitting of release data was found with first order, Higuchi and Peppas models and hence these models were selected for F-test statistics for ascertaining the mechanism of drug release. Higuchi model of drug release in DW and PBS of all the formulations was ruled out due to its significantly different F-value with other models. Thus, mechanism of release of flurbiprofen from ethylcellulose micropellets may be explained by the diffusional exponent model of Peppas et al. as ascertained by F-test statistics rather than the same, based on some other diffusional models even though they have shown good correlation.
Capsules↗
Evaluation of probucol as suppressor of ceftizoxime induced lipid peroxidation.
Considering drug induced lipid peroxidation, a possible mediator of drug induced toxicity and exploiting free radical scavenging action of probucol, which is a synthetic antioxidant of therapeutic interest, in vitro effects of the antioxidant on drug induced lipid peroxidation have been studied to explore its possible potential in reducing drug induced toxicity. In the present study, ceftizoxime sodium, a third generation of cephalosporin, has been taken as the representative drug and goat whole blood has been used as the lipid source. The study revealed that probucol could suppress drug induced lipid peroxidation to a significant extent. This provides scope for further study on probucol to evaluate its potential for reducing drug induced toxicity and increasing therapeutic index of drug by possible cotherapy.
Animals↗
A study on ceftriaxone-induced lipid peroxidation using 4-hydroxy-2-nonenal as model marker.
4-Hydroxy-2-nonenal, an indicator of lipid peroxidation process. was used as model marker to explore ceftriaxone-induced lipid peroxidation in goat liver homogenate. Ceftriaxone was found to induce lipid peroxidation significantly. It was further found that ascorbic acid could significantly arrest ceftriaxone-induced lipid peroxidation. The results corroborate the earlier findings with malondialdehyde as model marker.
Aldehydes↗
Evaluation of ascorbic acid as suppressor of cyclophosphamide induced lipid peroxidation using common laboratory markers.
The present study deals with exploration of lipid peroxidation induction capacity of cyclophosphamide, an anticancer drug, and in vitro evaluation of ascorbic acid as a suppressor of cyclophosphamide induced lipid peroxidation. Goat liver homogenate has been used as the lipid source. This evaluation was done by measuring the malondialdehyde, 4-hydroxy-2-nonenal, reduced glutathione and nitric oxide content of the tissue as markers of lipid peroxidation. The study revealed that ascorbic acid could suppress the drug induced lipid peroxidation to a significant extent.
Aldehydes↗