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The skin is an important barrier against environmental factors. Foregoing studies has shown that human KLK7 is a protease which promoted epidermal shedding, affected the epidermal barrier and increased the risk of atopic dermatitis. In this study, the structure and activity relationship of 40 human KLK7 inhibitors was explored by three-dimensional quantitative structure–activity relationship (3D-QSAR) and hologram quantitative structure–activity relationship (HQSAR). 3D-QSAR including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis fields (CoMSIA), and Topomer comparative molecular field analysis (Topomer CoMFA). From the data we got, the 3D-QSAR models (CoMFA with q2 = 0.755, r2 = 0.994; CoMSIA with q2 = 0.602, r2 = 0.980; Topomer CoMFA with q2 = 0.644, r2 = 0.929) and the HQSAR model (q2 = 0.717, r2 = 0.950) had a good predictability. Molecular docking was used to reveal the binding mode between the inhibitors and KLK7 protein further. 3D-QSAR, HQSAR, and molecular docking results also provided guidance for discovering new human KLK7 inhibitors. Finally, 13 new compounds were designed as potential human KLK7 inhibitors, and the predicted activity values showed an effective inhibition on human KLK7. [ABSTRACT FROM AUTHOR]

To have a better understanding of the relationship between structures and inhibitory activities of HIV fusion inhibitors, topomer comparative molecular field analysis (Topomer CoMFA) and hologram quantitative structure-activity relationship (HQSAR) were applied to study a series of pyrrole derivatives as potential HIV fusion inhibitors. Statistical results from the Topomer CoMFA model showed believable predictability based on the non-cross-validated value (r2 = 0.96), and the cross-validated value (q2 = 0.63). The r2 and q2 from the HQSAR model were 0.96 and 0.66, respectively, which also indicated the excellent predictability. External validations further proved the predictive potent of these two models with the rpred2 values of 0.96 for both the two models. Statistical results of the two models showed that they are all credible. In addition, we found a phenomenon that for some compound, bulky and negatively charged substitutions were favourable to its activity in the Topomer COMFA, but nitrogen contributed more positively than the bulkier and more negative chorine in the HQSAR. Therefore, in order to obtain more potential hits, the two models should be combined together. These studies would provide insights for the structure-activity relationship understanding of the small-molecule fusion inhibitors and be helpful for the rational design of novel fusion inhibitors in the future.Steric and electrostatics contour maps of compound A1 were analysed to have a further study on structure necessities of pyrrole derivatives as HIV-1 fusion inhibitor. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated gamma receptor is an attractive therapeutic target involving various types of metabolic syndrome. Viewing the importance of peroxisome proliferator-activated gamma receptor modulators, ligand and energetically optimized pharmacophores (e-pharmacophore), hologram-based quantitative structural activity relationships, and classification-based Bayesian models were developed, followed by molecular docking, mechanics, and dynamic analyses to search for essential structural requirements in the molecules for potent and selective peroxisome proliferator-activated gamma receptor modulation. Both ligand and e-pharmacophore models suggest that aromatic ring feature plays the crucial role, whereas the hologram-based quantitative structural activity relationships study indicates that phenyl and indole aromatic rings are essential scafolds for imparting selective peroxisome proliferator-activated gamma receptor modulation. Further, the e-pharmacophore model, molecular docking, and dynamics studies depict the importance of a carboxyl group for modulating peroxisome proliferator-activated gamma receptor agonistic activity through generating strong H-bonds with the active amino acid residues (His323, Tyr327, His449, and Tyr473, etc). The multi chemometrics modeling studies provide some insight into the prime structural features responsible for significant agonistic property of peroxisome proliferator-activated gamma receptor ligands. [ABSTRACT FROM AUTHOR]

Structure- and ligand-based computational design strategies were used to understand the molecular requirements of furanyl derivatives 2-(furan-2-yl)-[1,2,4]triazolo[1,5-f]pyrimidin-5-amines (TfPAs), 2-(furan-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine (TaPAs), and 2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amines (TTAs) as adenosine A receptor (AR) antagonists. First, we studied the structure-activity relationship of the selected compounds using hologram quantitative structure-activity relationship (HQSAR) methodology. The best model (training set included 67 compounds) included fragment parameters such as atoms (A), bonds (B), connections (C), and donors/acceptors groups (DA) and had a good q value of 0.776 including size fragments of 7-10 and the hologram length of 199. It also predicted adequately the compounds contained in the test set (10 compounds). In addition, we studied the binding orientations of the higher and less active compounds using flexible molecular docking. We found orientations that are in agreement with previous reports. [ABSTRACT FROM AUTHOR]

Validated comparative 2D- and 3D-QSAR modeling and docking studies were performed for forty-five quinolone carboxylic acids having cytotoxic, antiviral, and anti-HIV-1 IN activity. Statistically significant 2D-QSAR model was developed through MLR and PLS analyses on unsplitted as well as splitted dataset and validated. The models were validated on external set compounds. Chemical potential, Mulliken charge at C, and ETSA index at C are important for cytotoxicity. Global hardness, electrophilic frontier electron density at C, ETSA index at O, and C play pivotal role for antiviral activity. Mulliken charge at C, ETSA index at C, RTSA index at C, and C and LUMO density on C are important for anti-HIV-1 IN activity. HQSAR study suggested that maximum contributing fragments include C and C and substitutions at C and C for anti-HIV-1 IN activity and antiviral activity, respectively. The positively contributing fragments include C, C, C, C, and C are beneficial for cytotoxicity. CoMFA study suggested that favorable steric region located near C is important for anti-HIV-1 IN activity, steric factor at C substitution is important for antiviral and cytotoxicity activities. CoMSIA study correlates the steric region found in CoMFA study; hydrophobic favorable regions are located around C and near C. For antiviral activity, unfavorable hydrogen bond acceptor region is observed near C substitution, favorable hydrogen bond acceptor region is observed at N substitution. For cytotoxic activity, favorable electrostatic region is located around quinolone and benzene ring. Docking study suggested that Glu152, Gln148, and Asn155 residues of the HIV-1 integrase enzyme bind with the molecule. [ABSTRACT FROM AUTHOR]

A series of structurally related indole-5-carboxylic acids as potent inhibitors against human cytosolic phospholipase Aα (cPLAα) were subjected to hologram quantative structure-activity relationship (HQSAR) analysis. A training set containing 23 compounds served to establish the HQSAR model. The best HQSAR model was generated using atoms, bond, connectivity, donor and acceptor as fragment distinction, and 3-6 as fragment size with five components showing cross-validated q value of 0.790 and conventional r value of 0.961. The model was then employed to predict the potency of five test set compounds that were excluded in the training set, and a good agreement between the experimental and predicted values was observed exhibiting the powerful predictable capability of this model ( $$ r_{\text{pred}}^{ 2} = 0. 60 5 $$ ). Contribution maps indicated that the carboxylic acid moiety in position 5 of the indole scaffold and the electron-withdrawing effects contributed to the inhibitory activity. Based upon some key structural features derived from HQSAR 2D contribution maps, we have designed novel inhibitors of cPLAα possessing better inhibitory activity. [ABSTRACT FROM AUTHOR]

Designing compounds having good anti-tubercular activity is gaining much importance in the area of tuberculosis research due to the reemergence of antibiotic resistance strains. In this study, quantitative structure activity relationship (QSAR) of a group of 55 anti-tubercular agents with varying structures and potencies, CoMFA, Topomer CoMFA, and HQSAR studies have been performed on a series of antimycobacterial pyrroles. A training set containing 46 compounds served to establish the model and CoMFA was assessed by r value of 0.852 and cross-validated the q value of 0.614. In the Topomer CoMFA, r was 0.805, whole cross-validated q was 0.535. The predictive ability of CoMFA and Topomer CoMFA models was determined using a test set of 9 compounds, which gave the predictive correlation coefficients ( r) of 0.623 and 0.458, respectively. HQSAR was also carried out as a complementary study, and the best HQSAR model was generated using atoms, bond, connectivity, and hydrogen atoms as fragment distinction, 7-10 as fragment size and three components showing the cross-validated q value of 0.710 and conventional r value of 0.795. CoMFA, Topomer CoMFA steric, electrostatic, and HQSAR atomic contribution maps were generated to analyze the structural features of the datasets on that govern their inhibitory potency. Graphical Abstract: 3D and 2D-QSAR studies (CoMFA, Topomer CoMFA, HQSAR) of antimycobacterial pyrroles are described. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Chloroquine resistance is nowadays a great problem in malaria. Aurone derivatives were effective against chloroquine resistant parasite. Validated density functional theory (DFT)-based chemometric modeling, hologram QSAR (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity analysis (CoMSIA) studies were conducted on 35 aurone derivatives having antimalarial activity. 2D-QSAR models were developed on the training sets by Y-based ranking method. This model was validated on 50 pairs of the test and the training sets by k-Means cluster analysis method. HQSAR, CoMFA, and CoMSIA models were validated by standard techniques and each method validates the DFT-based 2D-QSAR study and in turn validates the earlier observed structural activity relationship data as well as each other. DFT-based 2D-QSAR model suggests that the increase of Mulliken charge at C and HOMO density located on C may be conducive to antimalarial activity. Ethyl group attached to C and the increase of the value of chemical potential may be beneficial for antimalarial activity. Methoxy fragment is important for better antimalarial activity by HQSAR study. CoMFA analysis shows a favorable steric green region is located near C whereas the unfavorable yellow region is far away from C. A large blue region located near C indicates the positively charged groups are favorable at this position. CoMSIA steric features correlates well with the CoMFA steric features. CoMSIA study suggests the bulky hydrophobic substitution at C is necessary for antimalarial activity. These results may be utilized to obtain potential antimalarial molecules. [ABSTRACT FROM AUTHOR]

β-Amyloid precursor protein cleavage enzyme (BACE) has been shown to be an attractive therapeutic target to control Alzheimer's disease (AD). Inhibition of β-secretase enzyme can prevent the deposition of Aβ (β-amyloid) peptides, which is thought to be the major cause of AD. The present study has been considered to explore 3D-QSAR, HQSAR, and pharmacophore mapping studies of BACE inhibitors. Contour maps of 3D-QSAR studies (CoMFA: R = 0.998, se = 0.067, Q = 0.765, R = 0.772, r = 0.739; CoMSIA: R = 0.992, se = 0.125, Q = 0.730, R = 0.713, r = 0.687) explain the importance of steric and electrostatic, along with hydrogen-bond (HB) acceptor and donor for binding affinity to BACE. HQSAR study ( R = 0.941, se = 0.326, Q = 0.792, R = 0.713, r = 0.709) indicates the important fragments of the molecular fingerprints that might be crucial for binding affinity. Pharmacophore space modeling ( R = 0.937, rmsd = 0.937, Q = 0.935, R = 0.709, r = 0.837) describes that HB acceptor, donor, hydrophobic, and steric are the important features for interaction with receptor cavity. Finally, the models are adjudged through the docking study elucidating the interactions between the receptor and the ligand, indicating the structural requirements of potent BACE inhibitors. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) plays a crucial role in the failure of cancer treatment with chemotherapeutic agents. In order to overcome the MDR, we have developed both 2D and 3D-QSAR models to enhance the structural requirement for P-gp inhibitors. In this work, hologram quantitative structure-activity relationship (HQSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of arylmethylamine-phenyl derivatives of P-gp inhibitors. The best predictions were obtained for HQSAR model ( q = 0.645, r = 0.772), CoMFA model ( q = 0.577, r = 0.917), and CoMSIA model (electrostatic, and H-bond donor) ( q = 0.610, r = 0.923). Statistical parameters from the generated QSAR models indicated that the data is well fitted and have high predictive ability. HQSAR result showed that donor and acceptor descriptors play an important role in P-gp activity, and methoxy group on the A-ring at R position is necessary for increasing activity. The CoMFA and CoMSIA models predicted that steric, electrostatic, and H-bond donor parameters are important for activity toward P-gp. Our theoretical results could be useful to design novel and more potent P-gp derivatives. [ABSTRACT FROM AUTHOR]

2D quantitative structure-activity relationships (2D QSAR) and hologram quantitative structure-activity relationship (HQSAR) studies were performed on a series of polysubstituted quinoline derivatives as inhibitors of phosphodiesterase 4 (PDE4). The dataset was divided into training set and test set by K-means clustering. 2D QSAR study was carried out using stepwise linear regression analysis, replacement method and enhanced replacement method. Statistically significant equations with high correlation coefficient ( R = 0.817) and low standard deviation (SD = 0.272) were obtained. The robustness of the models was confirmed with the help of leave one out cross validation ( R = 0.740), Y scrambling ( R = 0.374), and by predicting the activities of test molecules ( R = 0.627). A good correlation of topology, steric and polar features of polysubstituted quinoline derivatives with the PDE4 inhibitory activity was achieved. HQSAR calculations were carried out using various combinations of fragment size, hologram length and fragment type. The best HQSAR model was obtained with an R value of 0.952 and $$ R_{\text{cv}}^{2} $$ value of 0.783. The test-set of molecules was predicted by the HQSAR model. The results of 2D QSAR and HQSAR studies were used to design new molecules and to predict their activity using the developed models. [ABSTRACT FROM AUTHOR]

Plasmodium falciparum protein kinase 7 (PfPK7) is an important drug target for the development of anti-malarial treatment. In this study, hologram quantitative structure-activity relationship (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of imidazopyridazine derivatives of PfPK7 inhibitors. The best HQSAR model was obtained using atoms, connection, donor, and acceptor as fragment distinction parameter with fragment size (4-7) using a hologram length of 353 and 6 components ( q = 0.770, r = 0.964). The receptor-guided alignment has produced better statistical results for both CoMFA ( q = 0.590, r = 0.986) and CoMSIA ( q = 0.735, r = 0.988). The predictive ability of the developed models was further validated by a test set of eight compounds. HQSAR contribution map identified the presence of phenyl ring and cyclohexane moiety makes positive contribution for activity. Furthermore, CoMFA and CoMSIA contour maps suggested that additional bulky groups in cyclohexane moiety would increase the biological activity of PfPK7 inhibitors. Finally, these QSAR models were used to design new virtual molecules for imidazopyridazine derivatives and the results obtained from this study could be useful for further investigations. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is a clinical condition, diagnosed when ventricular dysfunction develops in diabetic patients without coronary atherosclerosis and hypertension. Intensive studies on pathogenesis of DCM show PKCβII as one of the mediators, responsible for developing DCM. 2D-QSAR (HQSAR) and 3D-QSAR (CoMSIA) studies were performed on a dataset of 42 anilino-monoindolylmaleimides acting as PKCβII selective inhibitors. Among the different alignment strategies used for CoMSIA study FlexS was found to be the best alignment method. Conformational search was performed for a few molecules to obtain the best model. CoMSIA analysis gave information about sites of favorable substitutions and steered us to assume that alkyl amine substitution on the pharmacophore would be a favorable substituent for improving the biological activity. From HQSAR studies we could extrapolate the presence of tertiary acceptor group may probably be responsible for increase in the activity whereas occurrence of cyclic ring structures would lead to decrease in the activity. [ABSTRACT FROM AUTHOR]