Combinatorial Protocol In Multiple Linear Regression Research Articles

2D-QSAR and molecular docking study on nitrofuran analogues as antitubercular agents

<abstract><sec> <title>Background</title> <p>Resistance to most of the antitubercular drugs has been on rising trends due to the misuse of existing drugs. This has encouraged us to explore a novel scaffold that has the potential for quick antimicrobial action with minimum side effects. Nitrofurans have attracted us due to their extensive biological activities, such as antibacterial and antifungal activities.</p> </sec><sec> <title>Objective</title> <p>The antitubercular activities of 126 nitrofuran derivatives have been investigated by using indicator parameters and topological and structural fragment descriptors.</p> </sec><sec> <title>Methods</title> <p>The different quantitative structure activity relationship (QSAR) models have been created and validated by using two different methodologies: combinatorial protocol in multiple linear regression (CP-MLR) and partial least-squares (PLS) analysis.</p> </sec><sec> <title>Results</title> <p>The 16 descriptors identified in CP-MLR are from six different classes: Constitutional, Functional, Atom Centered Fragments, Topological, Galvez, and 2D autocorrelation. Indicator parameters and Dragon descriptors suggested that the presence of a furan ring substituted by nitro group is essential for antitubercular activity. Further descriptors from constitutional, and functional classes suggest that the number of double bonds, number of sulphur atoms and number of fragments like thiazole, morpholine and thiophene should be minimum, along with the positive influence of Kier-Hall electrotopological states (Ss) for improved activity. The ACF class descriptors, GALVEZ class descriptors, and 2D-AUTO descriptor GATS4p have also shown positive influence on the antitubercular activity. The TOPO class descriptor T(O…S) suggests that the minimum gap between sulphur and oxygen is favorable for activity.</p> </sec><sec> <title>Conclusions</title> <p>The models acknowledged in the study have explained the variance between 72 to 76% in the training set and in the prediction of the test set compounds. Also, compounds <bold>122</bold>, <bold>123</bold> and <bold>82</bold> were found to possess good binding affinity towards nitroreductase.</p> </sec></abstract>

CP-MLR/PLS directed quantitative structure-activity relationship study on the histamine H3 receptor binding affinity: The cyclohexylamine based series

The histamine H3 receptor binding affinities of cyclohexylamine derivatives has been analysed with the topological and molecular features from Dragon software. Analysis of the structural features in conjunction with the biological endpoints in combinatorial protocol in multiple linear regression (CP-MLR) led to the identification of 26 descriptors for modelling the activity. The study clearly suggested the role of atomic properties such as mass, electronegativity or charge content, polarizability, atomic van der Waals volume, average valence connectivity index chi-5 and absence of number of acceptor atoms for H-bonds (N, O, F) type functionality to optimise the histamine H3 receptor binding affinity of titled compounds. The models developed and the participating descriptors advocate that the substituent groups of the cylohexylamine moiety hold scope for further modification in the optimization of the H3 receptor binding affinity. Analysis of these descriptors in partial least squares (PLS) highlighted their relative significance in modulating the biological response. The selected descriptors are enriched with information corresponding to the activity when compared to the remaining ones. Applicability domain analysis revealed that the suggested model matches the high quality parameters with good fitting power and the capability of assessing external data and all of the compounds was within the applicability domain of the proposed model and were evaluated correctly.

A Combined QSAR and Molecular Docking Approach for Identifying Pyrimidine Derivatives as Penicillin Binding Protein Inhibitors

Background:Antimicrobial resistance has been rising continuously in the past few years due to the overuse and exploitation of existing antimicrobials. This has motivated the search for a novel scaffold that has the capability of rapid antimicrobial action. The hybridized pyrimidines have attracted us due to their widespread biological activities, such as anti-bacterial and antifungal activities.Objective:The present study incorporates a series of pyrimidine-based antimicrobial agents for the 2D quantitative structure-activity relationship analysis (2D QSAR) and docking analysis.Methods:The exploration of the chemical structures in combination with the biological activity in CPMLR led to the detection of six descriptors (Constitutional descriptors, Topological descriptors, Modified Burden Eigenvalues and 2D autocorrelations) for modeling the activity. The resulted QSAR model has been validated using combinatorial protocol in multiple linear regression (CP-MLR) and partial least squares (PLS) analysis.Methods:The exploration of the chemical structures in combination with the biological activity in CPMLR led to the detection of six descriptors (Constitutional descriptors, Topological descriptors, Modified Burden Eigenvalues and 2D autocorrelations) for modeling the activity. The resulted QSAR model has been validated using a combinatorial protocol in multiple linear regression (CP-MLR) and partial least squares (PLS) analysis.Results:The best QSAR model displays the r2 t value of 0.594, Q2 LOO value of 0.779, Q2 L5O value of 0.767. Further docking study was executed using Autodock Vina against Penicillin-binding protein (PBP2a).Conclusion:From the results, Compounds 4, 11and 24 were found to possess a good binding affinity towards PBP2a.

A Quantitative Structure-Activity Relationship Study on a Series of Selective Non-zinc Binding Inhibitors of MMP13

Two novel series of potent and selective matrix metalloproteinase (MMP) inhibitors, involving unique binding mode at the active site and not interacting with the catalytic zinc, were collectively investigated to quantify their inhibition actions in relation with chemometric descriptors. Significant correlations, between their MMP13 inhibition activity and 2D-descriptors, were obtained through the combinatorial protocol in multiple linear regression (CP-MLR) computational procedure. The derived bi-variant models, validated internally and externally, were able to account for 86.5% of variance in the observed MMP13 inhibition activities. The filtered descriptors, from CP-MLR, satisfactorily explained the biological phenomenon under investigation. However the descriptors, MPC10, N-075 and C-030 accounting, respectively, for molecular path (bond) count of order 10, the structural fragments CH--N--CH and N--CH--N of aromatic ring remained prime to address the MMP13 inhibition actions of the compounds. From the highest significant correlations, it appeared that the higher value of MPC10 and absence of these aromatic ring fragments, are conducive in further improvement of MMP13 inhibition activity of a compound. The partial least squares (PLS) analysis has further confirmed the dominance of the identified descriptors. In the analysis, two-components remained optimum for these descriptors which are able to explain 89.3% of variances. Applicability domain (AD) analysis revealed that the suggested models have acceptable predictability. All the compounds remained within the AD of the proposed models and were evaluated correctly. Based on the inferences drawn from the study, some new analogues were suggested for further exploration. Their predicted MMP13 inhibition activities were much higher than the highest active congener of the original series.

Topological and Physicochemical Characteristics of 1,2,3,4-Tetrahydroacridin- 9(10H)-Ones and Their Antimalarial Profiles: A Composite Insight to the Structure-Activity Relation<sup>§</sup>

The study reports the QSAR rationales from multilateral approaches for the antimalarial activities (against W2 and TM90-C2B strains of Plasmodium falciparum) and physical properties (aqueous solubility, permeability and logD) of 1,2,3,4-tetrahydroacridin-9(10H)-one (THA) derivatives. A modification to Free-Wilson matrix (parameter set) is introduced to improve the compound to parameter ratio of the analysis carried out in the study. The models from modified Free-Wilson and physicochemical parameters suggest that 5(th) (R1) and 8(th) (R4) positions of THA scaffold should be free from substitution for the antimalarial activity against both the strains. The THA' s 6(th) (R2) and 7(th) (R3) positions' substituents with a blend of hydrophobicity and polarity offer scope to modulate the activities of these compounds. The substituent group contributions derived here gives opportunity to examine various combinations possible from these analogues. The models from the topological and other structural indices has suggested that MLOGP, LP1 and JGI6 as three common important features for activity against W2 and TM90 strains. The topological indices participated in the models suggested a preference for longer path lengths in molecules for better activity against both strains. The PLS analysis of the descriptors identified in the feature selection approach, combinatorial protocol in multiple linear regression (CP-MLR), has suggested that MATS3e and nRORPh are best suited to modulate the W2 activity, and Me, T(S..F) and ARR are best suited to modulate the TM90 activity. In these derivatives the analysis of aqueous solubility, permeability and logD has suggested that most of the R1 and R4 substituents have contributed with same arithmetic sign to theses properties. For all other variations in these compounds, the permeability increased with increasing logD and decreased with increasing aqueous solubility. The results suggest ways for the activity-property modulation in these analogues.

QSAR Rationale of Matrix Metalloproteinase Inhibition Activity in a Class of Carboxylic Acid Based Compounds

The matrix metalloproteinase-13 (MMP-13) inhibitory activities of carboxylic acid based compounds, in presence and absence of bovine serum albumin (BSA), have been analyzed quantitatively in terms of chemometric descriptors. The statistically validated quantitative structure-activity relationship (QSAR) models obtained through combinatorial protocol in multiple linear regression (CP-MLR) analysis and the participated descriptors in these models provided rationales to explain the inhibitory activities of these congeners. For MMP-13 inhibition activity, the identified descriptors (BEHm1, BELm1 and BEHm8) have highlighted the role of the atomic mass in terms of the highest and lowest eigenvalues derived from Burden matrix. The positive correlation with activity suggested that their higher values are desirable in improving the activity of a compound. Additionally, the descriptor C-027 representing R-CH-X type fragment in a molecular structure advocates the absence of such type of fragment for the improved activity. On the other hand presence of RCO-N< or >N-X=X type fragment (descriptor N-072) would be beneficiary to the MMP-13 inhibitory activity. The structural features, rationalized by the descriptors MSD (Balaban’s mean square distance index), nCrHR (number of ring tertiary C (sp3), H-047 (H attached to C1(sp3)/C0(sp2)) and H-050 (H attached to heteroatom) have imparted positive impact on the MMP-13 w/BSA inhibition activity. The atomic properties such as atomic polarizability and atomic Sanderson’s electronegativity have shown their positive impact on the activity via descriptors BELp4 and GATS3e in respective eigenvalues or lag. The other descriptors, MATS1m and MATS3e, have revealed the negative influence of atomic mass and electronegativity on the of MMP-13 w/BSA inhibition activity. The results obtained from CP-MLR analysis have been supported further through partial least-squares (PLS) study.

Chemometric Descriptor Based QSAR Rationales for the MMP-13 Inhibition Activity of Non-Zinc-Chelating Compounds

The MMP-13 inhibition activity of non-zinc-chelating compounds has been quantitatively analyzed in terms of chemometric descriptors. The statistically validated quantitative structure-activity relationship (QSAR) models provided rationales to explain the inhibition activity of these compounds. The descriptors, identified through combinatorial protocol in multiple linear regression (CP-MLR) analysis, have highlighted the role of 3-path Kier alpha-modified shape index (S3K), complementary information content index of 1-order neighborhood symmetry (CIC1), eigenvalue sum from mass weighted distance matrix (SEigm), lowest eigenvalue n. 6 of Burden matrix / weighted by atomic van der Waals volumes (BELv6) and by atomic polarizabilities (BELp6), 3-order topological charge index (GGI3) and the functionality, R--CR--R (C-025). From statistically validated models, it appeared that the descriptors S3K, BELv6, BELp6 and SEigm make positive contribution to activity and their higher values are conducive in improving the MMP- 13 inhibition activity of a compound. On the other hand, the descriptors CIC1, GGI3 and C-025 render detrimental effects to activity. Therefore, the absence of functionality, R--CR--R and lower values of descriptors CIC1 and GGI3 would be advantageous. PLS analysis has further corroborated the dominance of the CP-MLR identified descriptors. Applicability domain analysis revealed that the suggested models have acceptable predictability. All the compounds are within the applicability domain of the proposed models and were evaluated correctly.

CP-MLR/PLS-directed QSAR studies on the antimalarial activity and cytotoxicity of substituted 4-aminoquinolines

A QSAR study has been carried out on antimalarial activity and cytotoxicity of substituted 4-aminoquinolines using topological and structure descriptors from DRAGON software. The descriptors, relevant to each activity, were identified by Combinatorial Protocol in Multiple Linear Regression (CP-MLR) approach. The different descriptors were identified for the antimalarial activities and cytotoxicity. The antimalarial activities are correlated with Topological, 2D autocorrelation, and functional class descriptors. The cytotoxicity shows correlation with atom centered functional descriptors. The identified descriptors have been used for the development of QSAR models. The models suggested that analogs containing aromatic primary amines, aliphatic secondary amines, and devoid of aliphatic secondary amides would show better antimalarial activity. The presence of aromatic ethers, CH2R2, and CH3X molecular fragments contribute for cytotoxicity. The study gives a direction for the future exploration of the chemical space for 4-aminoquinolines to modulate antimalarial activity and cytotoxicity.

Modelling of serotonin reuptake inhibitory and histamine H3 antagonistic activity of piperazine and diazepane amides: QSAR rationales for co-optimization of the activity profiles

Selective human serotonin reuptake transporter (hSERT) inhibition is the first line of treatment to deal with the depression. In clinical practice for managing depression, the stimulants are co-prescribed to overcome cognitive impairment and fatigue. Recently, histamine H3 antagonists with serotonin reuptake inhibition activity have been proposed as alternative approach for the treatment of depression. In this context, a QSAR study of hSERT inhibitory and H3 antagonistic activity of piperazine and diazepane amide derivatives has been carried out using the combinatorial protocol in multiple linear regression (CP-MLR) with 0D- to 2D-Dragon descriptors. The derived QSAR models have provided a rational approach for the development of new piperazine and diazepane amide derivatives as hSERT inhibitors and H3 antagonists. In a concomitant partial least-squares (PLS) analysis of the hSERT and histamine H3 activities, the fraction contributions of identified descriptors revealed their importance in modulating these activities. The PLS analysis of other biological endpoints, namely hNET, hDAT, and histamine H3 activity in functional assay (H3pA2) of these analogues with the identified descriptors has further highlighted their scope in modulating these activities.

Consensus features of CP-MLR and GA in modeling HIV-1 RT inhibitory activity of 4-benzyl/benzoylpyridin-2-one analogues

The HIV-1 reverse transcriptase (RT) inhibitory activity of benzyl/benzoylpyridinones is modeled with molecular features identified in combinatorial protocol in multiple linear regression (CP-MLR) and genetic algorithm (GA). Among the features, nDB and LogP are found to be the most influential descriptors to modulate the activity. Although the coefficient of nDB suggested in favor of benzylpyridinones skeleton, the coefficient of LogP suggested the favorability of hydrophilic nature in compounds for better activity. The partial least squares analysis of the descriptors common to CP-MLR and GA has displayed their predictivity over the total descriptors identified in both the approaches. The back-propagation artificial neural networks model from the five most significant common descriptors (nDB, T(O..O), MATS8e, LogP, and BELp4) has explained 93.2% variance in the HIV-1 RT activity of the training set compounds and showed a test set r2 of 0.89. The results suggest that the descriptors have the ability to identify the patterns in the compounds to predict potential analogues.

A quantitative structure-activity relationship study on serotonin 5-HT6 receptor ligands: indolyl and piperidinyl sulphonamides

The serotonin 5-HT6 binding affinity of indolyl- and piperidinyl-sulphonamide derivatives has been analysed with topological and molecular features with DRAGON software. Analysis of the structural features in conjunction with the biological endpoints in combinatorial protocol in multiple linear regression (CP-MLR) led to the identification of 25 descriptors for modelling the activity. The study clearly suggested the role of an average Randic-type eigenvector-based index from adjacency matrix, VRA2, number of secondary aliphatic amines, nNHR, the sum of the topological distance between N and O, T(N···O), ring tertiary carbon atoms, nCrHR, and CH2RX type fragment, C-006, in a molecular structure to optimize the 5-HT6 binding affinities of titled compounds. The PLS analysis confirmed the dominance of information content of CP-MLR identified descriptors for modelling the activity when compared with those of leftover ones.

A rationale for the activity profile of benzenesulfonamide derivatives as cyclooxygenase (COX) inhibitors

The COX inhibition actions of benzenesulfonamides have been analyzed in terms of 0D-, 1D- and 2D-DRAGON descriptors using combinatorial protocol in multiple linear regression (CP-MLR). The derived QSAR models revealed that higher values of BEHm2 (the highest eigenvalue n.2 of Burden matrix) and C-009 (fragment CHRX2) and lower value of MATS2m (atomic masses weighted Moran autocorrelation of lag 2) are advantageous to the COX-2 inhibition activity. For a compound to be a potent COX-1 inhibitor, higher values of MATS6v (atomic van der Waals volumes weighted Moran autocorrelation of lag 6), GATS6p (atomic polarizabilities weighted Geary autocorrelation of lag 6), Hy (hydrophilic factor) and lower value of MATS5m (atomic masses weighted Moran autocorrelation of lag 5) are desirable.

CP-MLR/PLS directed QSAR study on apical sodium-codependent bile acid transporter inhibition activity of benzothiepines

The apical sodium-codependent bile acid transporter (ASBT) inhibition activity of benzothiepine derivatives have been analyzed based on topological and molecular features. Analysis of the structural features in conjunction with the biological endpoints in Combinatorial Protocol in Multiple Linear Regression (CP-MLR) led to the identification of 21 descriptors for modeling the activity. The study clearly suggested that the role of Randic shape index (path/walk ratio 3) and topological charges of 2-, 5-, and 6-orders to optimize the ASBT inhibitory activity of titled compounds. The influence of atomic van der Waals volumes, masses, Sanderson electronegativities, and polarizabilities are indicated via different lags of Moran and Geary autocorrelations. Presence of tertiary aromatic amine functionality in molecular structure has also shown its relevance in rationalizing the biological actions of benzothiepines. The PLS analysis has confirmed the dominance of information content of CP-MLR identified descriptors for modeling the activity when compared to those of the leftover ones.

Combinatorial protocol in multiple linear regression/partial least-squares directed rationale for the caspase-3 inhibition activity of isoquinoline-1,3,4-trione derivatives

The caspase-3 inhibition activity of isoquinoline-1,3,4-trione derivatives has been analysed with the topological and molecular features from Dragon software. Analysis of the structural features in conjunction with the biological endpoints in combinatorial protocol in multiple linear regression (CP-MLR) led to the identification of 45 descriptors for modelling the activity. The study clearly suggested the role of rotatable bonds, mean information on the distance degree equality, radial centricity, bond and structural information content of five-order neighbourhood symmetry, atomic van der Waals volumes and the presence or absence of certain structural fragments to optimise the caspase-3 inhibitory activity of titled compounds. The models developed and the participating descriptors advocate that the substituent groups of the isoquinoline moiety hold scope for further modification in the optimization of the caspase-3 inhibitory activity. Analysis of these descriptors in partial least squares (PLS) highlighted their relative significance in modulating the biological response. The selected descriptors are enriched with information corresponding to the activity when compared to the remaining ones.

Chemometric descriptors in modeling the carbonic anhydrase inhibition activity of sulfonamide and sulfamate derivatives

The carbonic anhydrase inhibition activities of sulfonamide and sulfamate derivatives have been quantitatively expressed in terms of MOE descriptors representing the 2D-features of compounds following combinatorial protocol in multiple linear regression (CP-MLR). The derived QSAR models have shown that partially charged and polarized surface areas in particular ranges, hydrophobicity, connectivity, information content, van der Waals surface area of the pharmacophore, and certain structural features such as the number of hydrogen and chlorine atoms, aromatic bonds of the molecules hold promise for rationalizing the different carbonic anhydrase inhibitory actions of titled compounds. The values, greater than 0.5 of parameters R(2)(p) and r(2)(m(test)), ensure that the predictions are reliable and acceptable. The derived significant models in such chemometric descriptors may be used to synthesize new potential compounds and to decipher possible mode of actions of these compounds at the molecular level.

Modeling of cyclooxygenase-2 and 5-lipooxygenase inhibitory activity of apoptosis-inducing agents potentially useful in prostate cancer chemotherapy: Derivatives of diarylpyrazole

The structure-activity models of the twenty derivatives for COX-2 and ten derivatives of 1,5-diarylpyrazole for 5-LOX inhibitory activity have been investigated using Combinatorial Protocol in Multiple Linear Regression (CP-MLR) with topological descriptors which were calculated from DRAGON software. Among the descriptor classes considered collectively in the study the COX-2 inhibitory activity was, however, correlated with topological (TOPO) and Galvez topological charge indices (GVZ). Modified Burden eigenvalues (BCUT) and 2D autocorrelations (2DAUTO) classes of descriptors have shown correlation to 5-LOX inhibitory activity. The developed models and participating descriptors in them have suggested that the substitutional modification in the diarylpyrazole moiety may have sufficient scope in optimization of prevailing inhibitory activities of these analogues.

Modeling of vascular endothelial growth factor receptor 2 (VEGFR2) kinase inhibitory activity of 2-anilino-5-aryloxazoles using chemometric tools

The structure-activity models of the VEGFR2 kinase inhibitory activity of the derivatives of 2-anilino-5-aryloxazole have been investigated using Combinatorial Protocol in Multiple Linear Regression (CP-MLR) with nearly 500 topological descriptors which were calculated from DRAGON software. Among the descriptor classes considered collectively in the study, the inhibitory activity was, however, correlated with simple functional (FUN), topological (TOPO), atom centered fragments (ACF), molecular walk counts (MWC) and 2D-autocorrelation (2D-AUTO) descriptors. The developed models and participating descriptors in them have suggested that the substitutional modifications in the 2-anilino-5-aryloxazole moiety may have sufficient scope in optimization of prevailing inhibitory activity of these analogues.

Topological descriptors in modeling malonyl coenzyme A decarboxylase inhibitory activity: N-Alkyl-N-(1,1,1,3,3,3-hexafluoro-2-hydroxypropylphenyl)amide derivatives

The malonyl-CoA decarboxylase (MCD) inhibition activity of derivatives of N-alkyl-N-(1,1,1,3,3,3-hexafluoro-2-hydroxypropylphenyl)amide has been analyzed through combinatorial protocolin multiple linear regression (CP-MLR) using different topological descriptors obtained from Dragon software for the energy minimized 3D-structures of these molecules. Among the topological descriptor classes considered in the study, the MCD inhibition activity is correlated with simple topological descriptors (TOPO) and 2D-autocorrelation descriptors (2DAUTO). The complementary information contents having neighborhood symmetry of 2-order, CIC2 from the TOPO class, the Geary autocorrelations-lag 8, weighted by atomic Sanderson electronegativities, GATS8e and the Moran autocorrelations-lag 6, weighted by atomic Sanderson electronegativities, MATS6e both from 2DAUTO class have contributed significantly in the development of a statistical significant model.

Topological descriptors in modeling the agonistic activity of human A 3 adenosine receptor ligands: The derivatives of 2-chloro- N6-substituted-4′-thioadenosine-5′-uronamide

The human A 3 adenosine receptor agonistic activity of 2-chloro- N 6-substituted-4′-thioadenosine-5′-uronamides has been analyzed through Combinatorial Protocol in Multiple Linear Regression (CP-MLR) using 488 topological descriptors obtained from DRAGON software for the energy minimized 3D-structures of these molecules. Among the various descriptor classes considered in the study, the human A 3 adenosine receptor agonistic activity is correlated with simple topological descriptors (TOPO), Modified Burden eigenvalues (BCUT) and functional group (FUNC) classes of descriptors. The average valence connectivity index of order zero, X0Av, the sum of topological distances between O and Cl, T (O⋯Cl) from the TOPO class, the lowest eigenvalue n.2 of Burden matrix/weighted by atomic masses, BELm2, from the BCUT class and the number of secondary aliphatic amides, nCONHR, from FUNC class have contributed significantly in the development of a statistical sound models. The models developed and the participating descriptors suggest that the substituent groups at N 6-position and/or 5′-uronamide of 2-chloro- N 6-substituted-4′-thioadenosine-5′-uronamide derivatives hold scope for structural modification in the optimization of activity.

QSAR study about ATP-sensitive potassium channel activation of cromakalim analogues using CP-MLR approach

The structure–activity models of the myorelaxant activity of the cromakalim analogues have been investigated with nearly 470 topological descriptors from DRAGON software using Combinatorial Protocol in Multiple Linear Regression (CP-MLR). Among the descriptor classes considered in the study, the binding affinity is correlated with simple functional (FUN), topological (TOPO), atom centered fragments (ACF), empirical (EMP), modified Burden eigenvalues (BCUT), Galvez topological charge indices (GVZ), 2D-autocorrelation (2D-AUTO) and constitutional (CONS) descriptors. The models developed, and the participating descriptors suggest that the substituent groups of 4,6-disubstituted-2,2-dimethylchromans hold scope for further modification in the optimization of activity. The higher path lengths rich in polarizability and lower path length rich in atomic mass in addition to the lower charge indices of the molecule are beneficiary to the activity. The participating descriptors also suggested that certain structural features such as carbon atoms attached to the heteroatom by single or multiple bonding, and lesser or ‘no’ branching in a molecule are helpful to augment the activity.