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According to the WHO, antimicrobial resistance is among the top 10 threats to global health. Due to increased resistance rates, an increase in the mortality and morbidity of patients has been observed, with projections of more than 10 million deaths associated with infections caused by antibacterial resistant microorganisms. Our research group has developed a new family of pyrimido-isoquinolin-quinones showing antibacterial activities against multidrug-resistant Staphylococcus aureus. We have developed 3D-QSAR CoMFA and CoMSIA studies (r2 = 0.938; 0.895), from which 13 new derivatives were designed and synthesized. The compounds were tested in antibacterial assays against methicillin-resistant Staphylococcus aureus and other bacterial pathogens. There were 12 synthesized compounds active against Gram-positive pathogens in concentrations ranging from 2 to 32 µg/mL. The antibacterial activity of the derivatives is explained by the steric, electronic, and hydrogen-bond acceptor properties of the compounds. [ABSTRACT FROM AUTHOR]

2,4-Disubstituted quinoline derivatives were designed based on a 3D-QSAR study, synthesized and evaluated for antimalarial activity. A large dataset of 178 quinoline derivatives was used to perform a 3D-QSAR study using CoMFA and CoMSIA models. PLS analysis provided statistically validated results for CoMFA (r2ncv = 0.969, q2 = 0.677, r2cv = 0.682) and CoMSIA (r2ncv = 0.962, q2 = 0.741, r2cv = 0.683) models. Two series of a total of 40 2,4-disubstituted quinoline derivatives were designed with amide (quinoline-4-carboxamide) and secondary amine (4-aminoquinoline) linkers at the -C4 position of the quinoline ring. For the purpose of selecting better compounds for synthesis with good pEC50 values, activity prediction was carried out using CoMFA and CoMSIA models. Finally, a total of 10 2,4-disubstituted quinoline derivatives were synthesized, and screened for their antimalarial activity based on the reduction of parasitaemia. Compound #5 with amide linker and compound #19 with secondary amine linkers at the -C4 position of the quinoline ring showed maximum reductions of 64% and 57%, respectively, in the level of parasitaemia. In vivo screening assay confirmed and validated the findings of the 3D-QSAR study for the design of quinoline derivatives. [ABSTRACT FROM AUTHOR]

In this paper, 3D-QSAR models were constructed to conduct a preliminary study on the structure–activity relationship of chrysin. The three-dimensional structures of the selected 54 chrysin derivatives were constructed by SYBYL-X 2.0 software, molecular mechanics procedures for conformational optimization, and molecular alignment. The 3D-QSAR model of these compounds was constructed by comparative molecular force field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), and the structure–activity relationships of chrysin compounds was preliminarily discussed. CoMFA and CoMSIA models are all constructed reasonably and reliably (CoMFA: q2 = 0.703, r2 = 0.886, SEE = 0.217, F = 113.572; CoMSIA: q2 = 0.647, r2 = 0.841, SEE = 0.255, F = 111.740), a series of three-dimensional contour maps were obtained to visualize the influence of various fields around the compound molecules on the drug activity. Groups with more hydrogen bonding acceptors attached to the end of the 7-O-alkane chain of chrysin are favorable for the molecular activity, such as amino acids. However, excessively long 7-O-alkane chains or the introduction of bulky hydrophobic groups on the 7-O-alkane chain will reduce the activity of the molecule. In contrast, the introduction of bulky hydrophobic groups on the side chains of amino acids will enhance the molecular activity. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is defined as a kind of breast cancer that lacks estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER2). This cancer accounts for 10–15% of all breast cancers and has the features of high invasiveness and metastatic potential. The treatment regimens are still lacking and need to develop novel inhibitors for therapeutic strategies. Three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses, based on a series of forty-seven thieno-pyrimidine derivatives, were performed to identify the key structural features for the inhibitory biological activities. The established comparative molecular field analysis (CoMFA) presented a leave-one-out cross-validated correlation coefficient q2 of 0.818 and a determination coefficient r2 of 0.917. In comparative molecular similarity indices analysis (CoMSIA), a q2 of 0.801 and an r2 of 0.897 were exhibited. The predictive capability of these models was confirmed by using external validation and was further validated by the progressive scrambling stability test. From these results of validation, the models were determined to be statistically reliable and robust. This study could provide valuable information for further optimization and design of novel inhibitors against metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Dihydropyrimidines are widely recognized for their diverse biological properties and are often synthesized by the Biginelli reactions. In this backdrop, a novel series of Biginelli dihydropyrimidines were designed, synthesized, purified, and analyzed by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. Anticancer activity against MCF-7 breast cancer cells was evaluated as part of their cytotoxicity in comparison with the normal Vero cells. The cytotoxicity of dihydropyrimidines ranges from moderate to significant. Among the 38 dihydropyrimidines screened, compounds 16 , 21 , and 39 exhibited significant cytotoxicity. These 3 compounds were subjected to flow cytometry studies and EGFRwt Kinase inhibition assay using lapatinib as a standard. The study included evaluation for the inhibition of EGFR and HER2 expression at five different concentrations. At a concentration of 1000 nM compound 21 showed 98.51 % and 96.79 % inhibition of EGFR and HER2 expression. Moreover, compounds 16 , 21 and 39 significantly inhibited EGFRwt activity with IC 50 = 69.83, 37.21 and 76.79 nM, respectively. In addition, 3D-QSAR experiments were conducted to elucidate Structure activity relationships in a 3D grid space by comparing the experimental and predicted cytotoxic activities. Molecular docking studies were performed to validate the results by in silico method. All together, we developed a new series of Biginelli dihydropyrimidines as dual EGFR/HER2 inhibitors. [Display omitted] • Multicomponent reactions help to swiftly synthesize and evaluate molecules for activity. • This research covers synthesis of 38 dihydropyrimidines and their activity against EGFR/HER2. • Novel dihydropyrimidines can be potential anticancer therapeutics. • Synthesized dihydropyrimidines are quite effective against breast cancer target. • Computational studies have been performed as predictive analysis to correlate with experimental studies. [ABSTRACT FROM AUTHOR]

Flavonoids are a class of phenolic and polyphenolic compounds widely distributed in vegetables, fruits, grains and herbs. Organic cation transporter 2 (OCT2) mediates the renal secretion of organic cations and is a key site of drug-drug interactions (DDIs). In this study, we systematically investigated the inhibitory effect of 28 flavonoids on OCT2-mediated uptake of 4–4-dimethylaminostyryl-N-methylpyridinium (ASP+). Among them, scullcapflavone II demonstrated the strongest inhibitory effect on OCT2-mediated uptake of ASP+ (IC 50 =11.2 μM) in a competitive manner. Next, 3D-QSAR analyses of flavonoid OCT2 inhibitors were performed using both CoMFA and CoMSIA models. The date revealed that bulky substituents at the C-3 and C-4 positions of ring C as well as the C-7 position of ring A could prevent the interactions of flavonoids with OCT2. In contrast, a hydrophilic and negatively charge substituent on ring A was favorable for the interactions of flavonoids with OCT2. Consequently, baicalin (IC 50 =220.2 μM) with a uronic acid substituent on ring A exhibited a stronger inhibition than baicalein (IC 50 =294.5 μM); quercetin-3-O-galactoside (IC 50 =497.4 μM) was a stronger inhibitor of OCT2 than rhamnetin 3-galactoside (IC 50 =1409.0 μM). Taken together, our findings could be valuable in elucidating and predicting the interactions of flavonoids with OCT2. [Display omitted] • Inhibitory effects of 28 flavonoids on OCT2 were investigated. • CoMFA and CoMSIA models were developed for flavonoids as OCT2 inhibitors. • Bulky substituents at C-3, C-4 positions of ring C or C-7 position of ring A were important. • Hydrophilicity of ring A contributes to the interactions of flavonoids with OCT2. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) is a promising target for the treatment of non-small cell lung cancer. Under crizotinib treatment, drug resistance and progressive disease appeared after the point mutations arising in the kinase domain of ALK. Second-generation ALK inhibitors can solve the deficiencies of the first generation, especially the drug resistance in cancer chemotherapy. Ceritinib (LDK378), a pyrimidine derivative, for example, can inhibit the activity of ALK with an IC50 value of 40.7 nmol/L, and can experience disease progression after initial treatment with crizotinib. Unfortunately, clear structure–activity relationships have not been identified to date, impeding the rational design of future compounds possessing ALK inhibition activity. To explore interesting insights into the structures of pyrimidine derivatives that influence the activities of the second-generation ALK inhibitors, three-dimensional quantitative structure–activity relationship (3D-QSAR) and molecular docking were performed on a total of 45 derivatives of pyrimidine. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques were used to generate 3D-QSAR models. CoMFA and CoMSIA were performed using the Sybyl X 2.0 package. Molecular docking analysis was performed using the Surflex-Dock module in SYBYL-X 2.0 package. We found in the CoMFA model that the non-cross-validated r2 value was 0.998, the cross-validated q 2 value was 0.663, and the F statistic value was 2,401.970, while the r2 value was 0.988; q 2 value was 0.730, and F value was 542.933 in CoMSIA models, suggesting the good predictability of the CoMFA and CoMSIA models. 3D contour maps and docking results suggested that different groups on the core parts of the compounds could enhance the biological activities. Based on these results, the established 3D-QSAR models and the binding structures of ALK inhibitors obtained favor the prediction of the activity of new inhibitors and will be helpful in the reasonable design of ALK inhibitors in the future.

In this paper, a three-dimensional quantitative structure-activity relationship (3D-QSAR) namely CoMFA and CoMSIA has been carried out on a series (43 compounds) of capsid assembly inhibitors on N-phenyl-3-sulfamoyl-benzamide-based. The statistical parameters from the models (CoMFA: r2 = 0.998, q2 = 0.625, r2pred = 0.837; CoMSIA: r2 = 0.987, q2 = 0.645, r2pred = 0.698) indicate that the data are well fitted and have high predictive ability. Molecular docking was employed to explore the binding mode between these compounds and the receptor protein, as well as help understand the structure-activity relationship revealed by CoMFA and CoMSIA. Contour maps of the QSAR models were generated and validated by molecular docking study. The final models of CoMFA/CoMSIA and molecular docking could be useful for the design and development of novel potent HBV capsid assembly inhibitors. [ABSTRACT FROM AUTHOR]

The emergence of multidrug resistance bacteria poses a great health theat. Therefore, it is a crucial demand to obtain new antibacterial drugs. Antimicrobial peptides (AMPs) have the characteristics of wide antimicrobial spectrum and lower drug resistance, hence, it is hopeful to substitute for classical antibiotics. In this study, two classic methods, comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), were used to analyze the structural feature of AMPs against Staphylococcus aureus or Escherichia coli, respectively. Subsequently, the models established by three-dimensional quantitative structure–activity relationships (3D-QSAR) (for S. aureus, CoMFA: Q2 = 0.512, R2 = 0.943, F = 59.916; CoMSIA: Q2 = 0.645, R2 = 0.993, F = 339.242; for E. Coli, CoMFA: Q2 = 0.507, R2 = 0.913, F = 66.862; CoMSIA: Q2 = 0.573, R2 = 0.966, F = 96.84) have good predictability and stability was constructed. Seven novel small AMPs were designed and synthesized based on the theoretical model. The novel AMPs showed potent antibacterial activity against S. aureus and E. coli while causing low host toxicity. This study provides a potential therapeutic option using 3D-QSAR models guiding the design and modification of novel AMPs, to address the prevalent infections caused by MDR bacterial. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is defined as a kind of breast cancer that lacks estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER2). This cancer accounts for 10–15% of all breast cancers and has the features of high invasiveness and metastatic potential. The treatment regimens are still lacking and need to develop novel inhibitors for therapeutic strategies. Three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses, based on a series of forty-seven thieno-pyrimidine derivatives, were performed to identify the key structural features for the inhibitory biological activities. The established comparative molecular field analysis (CoMFA) presented a leave-one-out cross-validated correlation coefficient q2 of 0.818 and a determination coefficient r2 of 0.917. In comparative molecular similarity indices analysis (CoMSIA), a q2 of 0.801 and an r2 of 0.897 were exhibited. The predictive capability of these models was confirmed by using external validation and was further validated by the progressive scrambling stability test. From these results of validation, the models were determined to be statistically reliable and robust. This study could provide valuable information for further optimization and design of novel inhibitors against metastatic breast cancer.

Rho-associated kinase-1 (ROCK1) has been recognized for its pivotal role in heart diseases, different types of malignancy, and many neurological disorders. Hyperactivity ofROCKphosphorylates the protein kinase-C (PKC), which ultimately induces smooth muscle cell contraction in the vascular system. Inhibition of ROCK1 has been shown to be a promising therapy for patients with cardiovascular disease. In this study, we have conducted molecular modeling techniques such as docking, molecular dynamics (MD), and 3-Dimensional structure-activity relationship (3D-QSAR) on a series of Nethyl- 4-(pyridin-4-yl)benzamide-based compounds. Docking and MD showed critical interactions and binding affinities between ROCK1 and its inhibitors. To establish the structure-activity relationship (SAR) of the compounds, 3D-QSAR techniques such as Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were used. The CoMFA (q² =0.774, r² =0.965, ONC = 6, and r²pred = 0.703) and CoMSIA (q² = 0.676, r² = 0.949, ONC = 6, and r²pred = 0.548) both models have shown reasonable external predictive activity, and contour maps revealed favorable and unfavorable substitutions for chemical group modifications. Based on the contour maps, we have designed forty new compounds, among which, seven compounds exhibited higher predictive activity (pIC50). Further, we conducted the MD study, ADME/Tox, and SA score prediction using the seven newly designed compounds. The combination of docking, MD, and 3D-QSAR studies helps to understand the coherence modification of existing molecules. Our study may provide valuable insight into the development of more potent ROCK1 inhibitors. [ABSTRACT FROM AUTHOR]

1,4-dihydropyridine derivatives (1,4-DHPs) are a class of drugs used to treat cardiovascular diseases, but these drugs can cause liver injury. To reveal the toxicity characteristics of these compounds, we used a series of assays, including cell viability, enzyme activity detection, and western blotting, to investigate the toxicity of seven kinds of 1,4-DHPs (0–100 μM) on HepG2 cells and establish 3D-QSAR model based on relevant toxicity data. After HepG2 cells were treated with 1,4-DHPs for 24 h, high-dose (100 μM) 1,4-DHPs decreased cell viability to varying degrees, while ROS and MDA contents were significantly increased, and ATP content was reduced. Moreover, with the concentration of 100 μM 1,4-DHPs (Nimodipine, Nitrendipine, Cilnidipine, and Manidipine) were markedly inhibited the phosphorylation levels of mTOR protein. The results of the 3D-QSAR model showed that the non-cross validation coefficient (R2) and cross validation coefficient (Q2) of the model were 0.982 and 0.652, respectively. Combined with external validation and the Williams diagram, the model showed good predictability and application domain. Based on the CoMSIA 3D contour map, the introduction of large volume and hydrogen bond receptor groups on the carbonyl oxygen side chains of the 1,4-DHPs ring 3- and 5- was beneficial for reducing the toxicity of 1,4-DHPs. The results of this study could supplement information on the cytotoxicity of 1,4-DHPs, and could provide theoretical support for predicting the toxicity of 1,4-DHPs. [Display omitted] • The model of 1,4-DHPs toxicity prediction is established by cytotoxicity test. • The method is used to predict the toxicity of 1,4-DHPs. • The model is built by the CoMSIA with good stability and predictive ability. [ABSTRACT FROM AUTHOR]

Abstract Background An alarming requirement for finding newer antidiabetic glitazones as agonists to PPARγ are on its utmost need from past few years as the side effects associated with the available drug therapy is dreadful. In this context, herein, we have made an attempt to develop some novel glitazones as PPARγ agonists, by rational and computer aided drug design approach by implementing the principles of bioisosterism. The designed glitazones are scored for similarity with the developed 3D pharmacophore model and subjected for docking studies against PPARγ proteins. Synthesized by adopting appropriate synthetic methodology and evaluated for in vitro cytotoxicity and glucose uptake assay. Illustrations about the molecular design of glitazones, synthesis, analysis, glucose uptake activity and SAR via 3D QSAR studies are reported. Results The computationally designed and synthesized ligands such as 2-(4-((substituted phenylimino)methyl)phenoxy)acetic acid derivatives were analysed by IR, 1H-NMR, 13C-NMR and MS-spectral techniques. The synthesized compounds were evaluated for their in vitro cytotoxicity and glucose uptake assay on 3T3-L1 and L6 cells. Further the activity data was used to develop 3D QSAR model to establish structure activity relationships for glucose uptake activity via CoMSIA studies. Conclusion The results of pharmacophore, molecular docking study and in vitro evaluation of synthesized compounds were found to be in good correlation. Specifically, CPD03, 07, 08, 18, 19, 21 and 24 are the candidate glitazones exhibited significant glucose uptake activity. 3D-QSAR model revealed the scope for possible further modifications as part of optimisation to find potent anti-diabetic agents.

Genetic mutations in APC or CNTBB1 gene with aberrant canonical Wnt/β-catenin pathway are responsible for more than 90% of colorectal carcinogenesis. Tankyrases (TNKS) are known to downregulate Wnt signaling by stabilizing AXIN protein through poly(ADP ribose)polymerization or PARSylation process and subsequently, promoting degradation of intracellular β-catenin. Tankyrase enzymes are modulated by a range of known inhibitors that bind individually to any of the nicotinamide or induced adenosine pockets or as dual binding antagonists. Hence, for designing dual tankyrase inhibitors as Wnt signaling antagonist; we carried out 3D-QSAR studies using a data set of 51 molecules of reported 3,4,5-trisubstituted 4H-1,2,4-triazole derivatives. These reported 51 molecules were divided into a training set (39 molecules) and test set (12 molecules), aligned and subjected to generate CoMFA, CoMSIA, and HQSAR models. CoMFA analysis showed q2 value of 0.694, r2ncv value of 0.991 and r2pred value of 0.641. Optimized CoMSIA analysis (SEHA) showed q2 value of 0.624, r2ncv value of 0.909 and r2pred value of 0.850. Both internal and external validations were performed for generated models of CoMFA and CoMSIA (SEHA) and satisfactory results were obtained. HQSAR analysis showed q2, r2, and r2pred values of 0.781, 0.901, and 0.811, respectively. Applicability domain was also found to be satisfactory with all compounds falling within the range and no outlier was observed. Contour maps from all studies provided significant results with identification of desired spatial arrangement of different atoms or functional groups in a molecule. Triazole ring system-based molecules were reported as potent tankyrase inhibitors. These noteworthy results were employed for the design of different triazole derivatives as potent tankyrase inhibitors, wherein a series of 20 different molecules were designed for evaluation of their potentials as novel tankyrase inhibitors. [ABSTRACT FROM AUTHOR]

Janus kinase 3 (JAK3) plays a critical role in the JAK/STAT signaling pathway and has become an attractive selective target for the treatment of immune-mediated disorders. Therefore, great efforts have been made for the development of JAK3 inhibitors, but developing selective JAK3 inhibitors remains a great challenge because of the high sequence homology with other kinases. In order to reveal the selective-binding mechanisms of JAK3 and to find the key structural features that refer to specific JAK3 inhibition, a systematic computational method, including 3D-QSAR, molecular dynamics simulation, and free energy calculations, was carried out on a series of JAK3 isoform-selective inhibitors. Necessary pharmacodynamic structures and key residues involved in efficient JAK3-inhibition were then highlighted. Finally, 10 novel JAK3 inhibitors were designed, the satisfactory predicted binding affinity to JAK3 of these analogous demonstrated that this study may facilitate the rational design of novel and selective JAK3 inhibitors.

In search of potent anti-mycobacterial agents, enoyl-ACP reductase enzyme found to be most probable due to its imperative role in type II fatty acid synthesis (FAS), while mycolic acid production in Mycobacterium tuberculosis (M. tuberculosis), which is the appropriate entity for the discovery of antimycobacterial agents due to its primary role in the metabolism. Hence, blocking of enoyl ACP reductase would be important to develop novel antitubercular drugs development. Pyrrole, which is one of the five membered heterocyclic moieties habitually institute in few of naturally occurring and organic products of various classes, plays a significant part in medicinal drug discovery. In this work, docking and 3D-QSAR (CoMFA and CoMSIA) studies were performed on a set of pyrrolyl phenoxy acetohydrazides. As per docking study, TYR158 and co-factor NAD+ are important amino acid residue at active site of enzyme for binding with the ligand. Among all the tested molecules, Compounds 4 and 28 have shown good docking scores of 7.08 and 8.85 respectively, steric and electrostatic field in CoMFA model displayed q2 = 0.511, r 2 = 0.822 while that of CoMSIA model displayed q2 = 0.625, r2 = 0.764 with the SEE values of of 0.314 and 0.607. Docking study revealed complete structurally imperative binding topographies between the pyrrole scaffolds and enoyl ACP reductase enzyme. Our studies offered useful information and evidence for designing of molecules with enhanced InhA inhibition. [ABSTRACT FROM AUTHOR]

JAK2 plays a critical role in JAK/STAT signaling pathway and in patho-mechanism of myeloproliferative disorders and autoimmune diseases. Thus, effective JAK2 inhibitors provide a promising opportunity for the pharmaceutical intervention of many diseases. In this work, 3D-QSAR study was performed on a series of 1-amino-5H-pyrido-indole-4-carboxamide derivatives as JAK2 inhibitors to obtain reliable comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) models with three different alignment methods. Among the different alignment methods, ligand-based (CoMFA: q2 = 0.676, r2 = 0.979; CoMSIA: q2 = 0.700, r2 = 0.953) and pharmacophore-based alignment (CoMFA: q2 = 0.710, r2 = 0.982; CoMSIA: q2 = 0.686, r2 = 0.960) has produced better statistical results when compared to receptor-based alignment (CoMFA: q2 = 0.507, r2 = 0.979; CoMSIA: q2 = 0.544, r2 = 0.917). Statistical parameters indicated that data are well fitted and have high predictive ability. The presence of electrostatic and hydrophobic field is highly desirable for potent inhibitory activity, and the steric field plays a minor role in modulating the activity. The contour analysis indicates ARG980, ASN981, ASP939 and LEU937 have more possibility of interacting with bulky, hydrophobic groups in pyrido and positive and negative groups in pyrazole ring. Based on our findings, we have designed sixteen molecules and predicted its activity and drug-like properties. Subsequently, molecular docking, molecular dynamics and DFT calculations were performed to evaluate its potency. [ABSTRACT FROM AUTHOR]

Macrocyclic ring structures could have drug-like properties such as membrane permeability, metabolic stability, binding affinity, selectivity, and high-biological activities. Synthesized macrocyclic inhibitors have been studied and the effect of ring size has gained attention from drug design community. Marsault et al. showed a positive correlation between ring size and inhibitory activity against rennin. On the other hand, De Clercq et al. suggested that there would be some optimum ring size for histone deacetylase inhibitory activity. Therefore, macrocyclic effects appear elusive while intriguing. In this study, we have selected a large set of macrocyclic inhibitors (14–20-membered rings) to study macrocyclic effect on MerTK using molecular modeling techniques. We carefully positioned all the cyclic inhibitors into the binding pocket utilizing available information obtained from both experimental and theoretical means. Then, from the resultant binding poses, the ligand–receptor interactions were analyzed. Unlike previous reports, we could not observe any relevance between ring size and inhibitory activity. However, there is a correlation between the number of hydrogen bonds and inhibitory activity. Among these hydrogen-bonding interactions, active site residues Arg727, and Asn728 as well as two signature interactions at the hinge region were found to be crucial for MerTK inhibition. Furthermore, the importance of number of hydrogen bonding was further validated statistically by means of 3D-QSAR techniques such as CoMFA and CoMSIA. The involvement of Arg727 and Asn728 was checked graphically by CoMSIA hydrogen-bonding donor map. This outcome could be helpful for more potent MerTK inhibitor design. In addition, more detailed studies on ring size effect would be desirable to understand macrocyclic effects. [ABSTRACT FROM AUTHOR]

The 5-hydroxytryptamine (5-HT1A) receptors represent an attractive target in drug discovery. In particular, 5-HT1A agonists and partial agonists are deeply investigated for their potential role in the treatment of anxiety, depression, ischaemic brain disorder and more recently, of pain. On the other hand, 5-HT1A antagonists have been revealed promising compounds in cognition disorders and, lately, in cancer. Thus, the discovery of 5HT1A ligands is nowadays an appealing research activity in medicinal chemistry. In this work, Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) were applied on an in-house library of 5-HT1A ligands bearing different chemical scaffolds in order to elucidate their affinity and selectivity for the target. Following this procedure, a number of structural modifications have been drawn for the development of much more effective 5-HT1AR ligands.

Respiratory syncytial virus (RSV) has been identified as a main cause of hospitalisation in infants and children. To date, the current therapeutic arsenal is limited to ribavirin and palivizumab with variable efficacy. In this work, starting from a number of in-house series of previously described anti-RSV agents based on the benzimidazole scaffold, with the aim at gaining a better understanding of the related chemical features involved in potency and safety profiles, we applied a computational study including two focussed comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The results allowed us to derive useful suggestions for the design of derivatives and also to set up statistical models predicting the potency and selectivity index (SI = CC50/EC50) of any new analogue prior to synthesis. Accordingly, here, we discuss preliminary results obtained through the applied exhaustive QSAR analyses, leading to design and synthesise more effective anti-RSV agents.

ERRγinverse agonist is a powerful therapeutic target for the treatment of cancers and certain metabolic disorders. Until now, only GSK5814 was reported as selective ERRγinverse agonist. So 60 newly hydroxytamoxifen analogues were selected to perform molecular docking and 3D-QSAR study to design more selective inverse agonist of ERRγ. Both established CoMFA and CoMSIA models obtained high predictive and satisfactory value, demonstrated that bulky, hydrophobic and negative electrostatic substitutions are preferred at R2 position, and introducing hydrophilic and H-bond donor and acceptor groups at R1 and R4 positions is greatly important for improving binding activities. The obtained information will be useful to provide clues for rationally designing novel and high potency ERRγinverse agonists. [ABSTRACT FROM AUTHOR]

Oxytocin plays a vital role in the occurrence of preterm birth by interacting with oxytocin receptor (OTR), and thus OTR antagonists provide effective approaches for the treatment of early birth. Presently, for purpose of exploring the structural traits affecting the antagonism potency, the up-to-date largest set of 121 2,5-diketopiperazine derivatives as OTR antagonists was subjected to ligand-based three-dimensional quantitative structure–activity (3D-QSAR) analysis applying comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. The resultant optimal CoMSIA model displays proper validity and predictability with cross-validated correlation coefficient Q2 = 0.614, non-cross-validated correlation coefficient R2 ncv = 0.969 and predicted correlation coefficient R2 pre = 0.912 for the test set of compounds, respectively. In addition, docking study was carried out for further elucidating the binding modes of OTR antagonists. The final docking cavity was located among the TM2-TM7 helices of the target protein and proved to be the same as described by other scholars' researches of other type of OTR antagonists. The major amino acids forming the cavity are Q92, Q96, K116, Q119, V120, M123, G196, I201, Q295, W288, F311 and M315. Representative compound 118 forms two H-bonds with Q119 and two H-bonds with Q295, with also a π - π stacking effect with F311, respectively. Meanwhile, as a supplementary tool to study the antagonists' conformation in the binding cavity, molecular dynamics (MD) simulation was also performed to further elucidate the changes in the ligand-receptor complex. We hope that the obtained models and information may help to provide an insight into the interaction mechanism of OTR antagonists and facilitate the design and optimization of novel antagonists for preventing premature birth. Image 1 • Oxytocin receptor antagonists are effective for preventing preterm labour. • Structural traits affecting antagonism potency were explored. • Crucial amino acids for antagonists binding of OTR were discovered. • Binding conformation of 2,5-diketopiperazine derivatives were analyzed. [ABSTRACT FROM AUTHOR]

Phosphodiesterase-5 (PDE5) inhibitors can be used as clinical agents for the treatment of erectile dysfunction and pulmonary hypertension. A series of aryl-chromeno-pyrrol derivatives were previously identified as PDE5 inhibitors in our lab. Herein, these molecules were subjected to 3D-QSAR analysis with CoMFA and CoMSIA methods to gain deeper insight into the structural requirements for their bioactivities. Receptor- and ligand-based alignment were used and compared to find the alignment-related factors that affect the accuracy of QSAR models. The receptor-based CoMFA and CoMSIA models, which were generated by superimposing the docking conformations directly in the protein binding site, gave more significant results for 38 training set compounds and 5 test set molecules. Comparison of the two alignments revealed that spatial arrangement of the ligands is the principal factor in determining the reliability of the 3D-QSAR models. Detailed analysis of the receptor-based CoMSIA-SE contour maps provided much helpful information to improve the bioactivities of aryl-chromeno-pyrrol analogs as PDE5 inhibitors. [ABSTRACT FROM AUTHOR]

In Quantitative Structure‐Activity Relationship (QSAR) studies, selection of an appropriate method to assign the partial charge is crucial to derive a reliable model. The prediction accuracy of 3D‐QSAR models depends mainly on the method by which the partial charges were calculated. Therefore, we are interested in examining the effects of empirical and semi‐empirical partial charges on 3D‐QSAR methods, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The feasibility and performance of these charges have been tested on Janus Kinase 2 inhibitors. Both empirical (Gasteiger‐Huckel, Del‐Re, Gasteiger Marsili, Huckel, Merck Molecular Force Field 94 (MMFF94), Pullman) and semi‐empirical (Austin Model 1 (AM1), Parameterized Model 3 (PM3), Recife Model 1 (RM1), and Modified Neglect of Diatomic Overlap (MNDO)) charges exhibited statistically significant quality. Among them, MMFF94, MNDO and AM1 charges yielded higher cross‐validation correlation coefficient (q2) values whereas Del‐Re and MMFF94 charges produced topmost predictive ability (r2pred). Overall, MMFF94 in CoMFA and MMFF94 and MNDO in CoMSIA models was found to be the best charges when both q2 and r2pred values were used as an evaluation criterion. Our results could provide an idea of selection of appropriate charge rather than using default charge to enhance the quality of 3D‐QSAR when prediction accuracy and predictive ability were employed. [ABSTRACT FROM AUTHOR]

Abstract As a kind of potential anticancer compounds, Cyclin-dependent kinase (CDK) inhibitors have receved great attention in recent years. In order to deep research the bioactivity and corresponding key influence factors of CDK8/19 inhibitors on molecular level, quantum chemistry and 3D-QSAR have been performed on 64 molecules based on pyridine ring scaffold. Two high predictive QSAR models have been built, in which both the CoMFA model (q2 = 0.69, r2 = 0.98) and CoMSIA model (q2 = 0.61, r2 = 0.98) have displayed quite good external predictablility on test set with excellent values of r p r e d 2 (0.94 and 0.97). In these models, the steric, electrostatic and hydrophobic fields have played key roles on bioactivity. Docking simulation has been carried out to further investigate possible binding modes of compounds into the active site of CDK8 (PDB. 5I5Z), the results show that some high bioactivity molecules are quite well embedded in the active pocket. Nitrogen-atom of pyridine ring and some other groups (ie. NH, CO, SO. NH, CO, SO) have formed medium strength hydrogen bonds (1.5 Å to 2.2 Å) with the N, H, O atoms of the protein. The geometric structures of the inhibitor molecules have been changed differently during the processes of docking, surflex-dock has confirmed the acting force stability of predicted molecules in the protein. Our method and results can be helpful for finding new targets and developing new drugs. Graphical abstract 3D-surface of active site of CDK8 (pdb:5I5Z) included compound 28. Image 1 Highlights • The 3D-QSAR and molecular docking were carried out to study the CDK8 inhibitors. • All calculations were conducted using the Gaussian 09 program package. • QSAR models have excellent external predictive ability. • New compounds were designed and their biological activity were predicted by using built models. • The docking results among the existing CDK8 inhibitors and the target compounds were compared. [ABSTRACT FROM AUTHOR]

Graphical abstract 3D-QSAR methods were innovatively applied to correlate the field-based descriptors with the separation efficiencies of substituted cupferrons. Highlights • 3D-QSAR first introduced into the structure-activity relationship of flotation collectors. • Hydrophobic effect, steric effect and electrostatic interaction considered simultaneously. • Theoretically predicted separation efficiencies match with experimentally observed values. • Novel cupferron-based molecules with potentially higher performance proposed. Abstract Three-dimensional quantitative structure-activity relationship (3D-QSAR) methods were innovatively introduced into the structure-performance study of flotation collectors using topomer comparative molecular field analysis (Topomer CoMFA) and comparative molecular similarity indices analysis (CoMSIA). A total of eighteen cupferron derivatives was used to build up the 3D-QSAR models. The resultant Topomer CoMFA and CoMSIA models are both statistically significant. The Topomer CoMFA model yielded the non-cross-validated correlation coefficient (r 2) and the leave-one-out correlation coefficient (q 2) of 0.931 and 0.707, respectively. The corresponding r 2 and q 2 of the CoMSIA model were 0.816 and 0.651, respectively. The theoretically predicted separation efficiencies are in excellent agreement with the experimentally measured values, validating the high predictive ability of the 3D-QSAR models. Valuable information concerning the hydrophobic, steric and electrostatic properties of substituted cupferrons has been obtained and analysed in detail. The 3D-QSAR contour maps indicate that the aliphatic chains with significant hydrophobicity together with electron rich groups at 4-position of the benzene are of utmost importance for the flotation performance of substituted cupferrons. The addition of the electron-withdrawing group to the 2, 3-positions of the benzene ring is undesirable for enhancing the separation efficiencies. Structural modification of substituted cupferrons has been evaluated and novel cupferron derivatives with theoretically improved separation efficiency have been proposed. Despite the fact that 3D-QSAR methods have matured into a wide variety of applications such as drug discovery, catalyst science, environmental science, pesticide science, computational toxicology and material science, this work is the first attempt of introducing 3D-QSAR into the structure-activity relationship of flotation collectors. The generated 3D-QSAR models in this work could provide a new perspective on the structure-activity relationship of flotation collectors and potentially hold great promise for the rational design, selection and prediction of untested flotation collectors through virtual screening of chemical database. [ABSTRACT FROM AUTHOR]

BTK inhibitors have been proved as an effective target for B-cell malignancies. Ibrutinib is the most advanced irreversible BTK inhibitor for treating mantle cell lymphoma/chronic lymphocytic leukaemia but with existing drug resistance and adverse effects. To design novel effective and safety reversible BTK inhibitors, 115 newly cinnoline analogues were selected to perform molecular docking and 3D-QSAR study because of the main scaffold similarity to Ibrutinib. Both established CoMFA and CoMSIA models obtained high predictive and satisfactory value. CoMFA/CoMSIA contour maps demonstrated that bulky substitutions are preferred at R1 and R3 positions, and introducing hydrophilic and negative electrostatic substitutions at R1 positions is important for improving BTK inhibitory activities. These results will be useful to provide clues for rationally designing novel and high potency BTK inhibitors. [ABSTRACT FROM AUTHOR]

Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q2 (cross-validated correlation coefficient) = 0.557, R2ncv (non-cross-validated correlation coefficient) = 0.740, R2pre (predicted correlation coefficient) = 0.749 and Q2 = 0.598, R2ncv = 0.767, R2pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors.

The bromodomain containing protein 4 (BRD4) recognizes acetylated histone proteins and plays numerous roles in the progression of a wide range of cancers, due to which it is under intense investigation as a novel anti-cancer drug target. In the present study, we performed three-dimensional quantitative structure activity relationship (3D-QSAR) molecular modeling on a series of 60 inhibitors of BRD4 protein using ligand- and structure-based alignment and different partial charges assignment methods by employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The developed models were validated using various statistical methods, including non-cross validated correlation coefficient (r2), leave-one-out (LOO) cross validated correlation coefficient (q2), bootstrapping, and Fisher’s randomization test. The highly reliable and predictive CoMFA (q2 = 0.569, r2 = 0.979) and CoMSIA (q2 = 0.500, r2 = 0.982) models were obtained from a structure-based 3D-QSAR approach using Merck molecular force field (MMFF94). The best models demonstrate that electrostatic and steric fields play an important role in the biological activities of these compounds. Hence, based on the contour maps information, new compounds were designed, and their binding modes were elucidated in BRD4 protein’s active site. Further, the activities and physicochemical properties of the designed molecules were also predicted using the best 3D-QSAR models. We believe that predicted models will help us to understand the structural requirements of BRD4 protein inhibitors that belong to quinolinone and quinazolinone classes for the designing of better active compounds. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase 1B (PTP1B) is an intracellular non-receptor phosphatase that is implicated in signal transduction of insulin and leptin pathways, thus PTP1B is considered as potential target for treating type II diabetes and obesity. The present article is an attempt to formulate the three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling of a series of compounds possessing PTP1B inhibitory activities using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The optimum template ligand-based models are statistically significant with great CoMFA (R 2 cv  = 0.600, R 2 pred  = 0.6760) and CoMSIA (R 2 cv  = 0.624, R 2 pred  = 0.8068) values. Molecular docking was employed to elucidate the inhibitory mechanisms of this series of compounds against PTP1B. In addition, the CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of PTP1B active site. The knowledge of structure-activity relationship and ligand-receptor interactions from 3D-QSAR model and molecular docking will be useful for better understanding the mechanism of ligand-receptor interaction and facilitating development of novel compounds as potent PTP1B inhibitors. [ABSTRACT FROM AUTHOR]

Resveratrol (3,4′,5-trihydroxystilbene) has been reported to promote degradation of intracellular amyloid-beta (Aβ) aggregates in Alzheimer’s disease (AD). In the present paper, we report comparative molecular field analysis (CoMFA)-based and comparative molecular similarity indices analysis (CoMSIA)-based three-dimensional quantitative structure-activity relationship (3D-QSAR) study of 30 resveratrol derivatives. The best predictive CoMFA model with correlation coefficients (r2) of 0.905 and 0.908 for training and test sets, respectively, and cross-validated correlation coefficient (q2) of 0.713 was obtained using training and test set of 20 and 10 compounds, respectively. Using the same sets of compounds, the best CoMSIA model exhibiting steric, electrostatic, and hydrophobic fields revealed r2 values of 0.938 and 0.966 for training and test sets, respectively, and q2 value of 0.726. The features obtained from contour maps of both CoMFA and CoMSIA models were used to design a library of hybrid resveratrol derivatives based on a set of six potent Aβ aggregation inhibitors. The inhibitory potential of the most active compound of this library was found to be close to that of the most active compound of the data set. The results obtained from the present study makes a foundation for the development of effective drugs against Aβ aggregation. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is becoming a global pandemic disease. As an important target for the generation and development of diabetes mellitus, peroxisome proliferator-activated receptor γ (PPARγ) has been widely studied. PPARγ agonists have been designed as potential anti-diabetic agents. The advanced development of PPARγ agonists represents a valuable research tool for diabetes therapy. To explore the structural requirements of PPARγ agonists, three-dimensional quantitative structure–activity relationship (3D-QSAR) and molecular docking studies were performed on a series of N-benzylbenzamide derivatives employing comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and surflex-dock techniques. The generated models of CoMFA and CoMSIA exhibited a high cross-validation coefficient (q2) of 0.75 and 0.551, and a non-cross-validation coefficient (r2) of 0.958 and 0.912, respectively. The predictive ability of the models was validated using external validation with predictive factor (r2pred) of 0.722 and 0.682, respectively. These results indicate that the model has high statistical reliability and good predictive power. The probable binding modes of the best active compounds with PPARγ active site were analyzed, and the residues His323, Tyr473, Ser289 and Ser342 were found to have hydrogen bond interactions. Based on the analysis of molecular docking results, and the 3D contour maps generated from CoMFA and CoMSIA models, the key structural features of PPARγ agonists responsible for biological activity could be determined, and several new molecules, with potentially higher predicted activity, were designed thereafter. This work may provide valuable information in further optimization of N-benzylbenzamide derivatives as PPARγ agonists. [ABSTRACT FROM AUTHOR]

Mechanistic target of rapamycin is involved in the formation of tumor microvasculature was an ideal target for computer-aided drug design. The predictive study of quantitative structure-activity relationship and molecular docking can shorten the cycle and reduce the cost of designing the higher activity mTOR inhibitors. In this article, comparative molecular field analysis and comparative molecular similarity indices analysis fields were used to analyse three-dimensional quantitative structure-activity relationship model. The model (comparative molecular similarity indices analysis with q2=0.607, r2=0.909; comparative molecular similarity indices analysis with q2=0.703, r2=0.935) has a good predictability. Three-dimensional quantitative structure-activity relationship model contour maps indicate the electrostatic, hydrophobic and hydrogen bond donor fields have crucial effects to derivatives biological activity. Molecular docking was employed to explore the conformations of 55 compounds with key amino acid residues. Finally, combining contour maps with molecular docking results, ten derivatives as potential mechanistic target of rapamycin inhibitors were designed to further verify established three-dimensional quantitative structure-activity relationship models. These data provide significant theoretical foundation for designing better activity mechanistic target of rapamycin inhibitors. [ABSTRACT FROM AUTHOR]

In the present study, we have employed the ligand-based drug design technique, 3D-QSAR, through a comparative molecular field analysis (CoMFA) and a comparative molecular similarity indices analysis (CoMSIA) to determine the key factors for the plant growth promoting activity of brassinosteroids reported in literature, using the bean second-internode bioassay measured on two groups of compounds with different molar concentrations. This is the first 3D-QSAR study using the second internode elongation as biological activity. These results provide useful ideas for the design of new molecules, which could be explored in the future to identify novel vegetable growth promoters with similar or greater biological activity than natural brassinosteroids. The reliability of this study was supported by the robust statistical parameters obtained from CoMFA (Model A, r²pred = 0.751; Model B, r²pred = 0.770) and CoMSIA (Model A, r²pred = 0.946; Model B, r²pred = 0.923) analysis. [ABSTRACT FROM AUTHOR]

Rho Kinases (ROCK) has been found to regulate a wide range of fundamental cell functions such as contraction, motility, proliferation, and apoptosis. Recent experiments have defined new functions of ROCKs in cells, including centrosome positioning and cell-size regulation, which might contribute to various physiological and pathological states. In this study, we have performed pharmacophore modeling and 3D QSAR studies on a series of 36 indoles and 7-azoindoles derivatives as ROCK2 inhibitors to elucidate the structural variations with their inhibitory activities. Ligand based CoMFA and CoMSIA models were generated based on three different alignment methods such as systematic search, simulated annealing and pharmacophore. A total of 15 CoMFA models and 27 CoMSIA were generated using different alignments. One model from each alignment is selected based on the statistical values. Contour maps of the selected models were compared, analysed and reported. The 3D QSAR study revealed that electro positive group linked to the methoxy-benzene ring position of the structure will enhance the biological activity and bulkier substitutions are preferred in the methyl dihydroindole region. Also, it is found that the hydrogen bond donor substituted at the R 1 position enhances the inhibitory activity. In future, this study would give proper guidelines to further enhance the activity of novel inhibitors for ROCK2. [ABSTRACT FROM AUTHOR]

Caspase-3 has become an attractive target in the treatment of many diseases such as Alzheimer, Parkinson’s, myocardial infarction and cancer. In the present study, molecular three-dimensional quantitative structure activity relationship (3D-QSAR) and docking studies were performed on a series of caspase-3 activators. Comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and step-wise k-nearest neighboring molecular field analysis [(SW) kNN MFA] were performed to gain insight into the key structural factors affecting the activity. The results of 3D-QSAR are reliable and significant having high predictive (q2) ability showing good correlation between predicted and observed activity. The lower value of standard error of estimation shows that most of the observed values cluster fairly close to the regression line. Molecular docking was performed with the GOLD docking program used to explore the binding mode between the ligands and the receptor.

3D-QSAR (comparative molecular field analysis (CoMFA)) and comparative molecular similarity indices analysis (CoMSIA) were performed on novel 2,5 disubstituted 1,3,4-oxadiazoles analogues as anti-fungal agents. The CoMFA and CoMSIA models using 13 compounds in the training set gives Q 2 values of 0.52 and 0.51 respectively, while R 2 values of 0.92. The adapted alignment method with the suitable parameters resulted in reliable models. The contour maps produced by the CoMFA and CoMSIA models were employed to determine a three-dimensional quantitative structure–activity relationship. Based on this study a set of new molecules with high predicted activities were designed. Surflex-docking confirmed the stability of predicted molecules in the receptor. [ABSTRACT FROM AUTHOR]

We recently reported a series of 39 weakly basic N -arylsulfonylindoles as novel 5-HT 6 antagonists. Eight of the compounds exhibited moderate to high binding affinities, with 2-(4-(2-Methoxyphenyl)piperazin-1-yl)-1-(1-tosyl-1 H -indol-3-yl)ethanol 16 showing the highest binding affinity (p K i = 7.87). Given these encouraging results and as a continuation of our research, we performed an extensive step-by-step search for the best 3D-QSAR model that allows us to rationally propose novel molecules with improved 5-HT 6 affinity based on our previously reported series. A comparative molecular similarity indices analysis (CoMSIA) model built on a docking-based alignment was developed, wherein steric, electrostatic, hydrophobic and hydrogen bond properties are correlated with biological activity. The model was validated internally and externally (q 2 = 0.721; r 2 pred = 0.938), and identified the sulfonyl and hydroxyl groups and the piperazine ring among the main regions of the molecules that can be modified to create new 5-HT 6 antagonists. [ABSTRACT FROM AUTHOR]

The preceding years have brought an exponential increase in our understanding of the endocannabinoid system (ECS), including the knowledge of CB1 and CB2 cannabinoid receptors, endocannabinoids, and the enzymes that synthesize and degrade endocannabinoids. Among these ECS components CB2 receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential to treat numerous pathologies while avoiding the adverse psychotropic effects that can accompany CB1 receptor–based therapies. Recently, our research group has reported a new series of non-cytotoxic benzo[ d ]imidazoles and benzo[ b ]thiophenes displaying high CB2/CB1 selectivity index. In order to investigate the structural requirements for CB2 ligands and to derive a predictive model that can be used for the design of novel selective CB2 ligands, a three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on the above mentioned chemical series employing comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques. The CoMFA and CoMSIA models displayed high external predictability (r pred 2 0.919 and 0.908) and good statistical robustness. Valuable information regarding the steric, electrostatic and hydrophobic properties of the molecules was obtained, and several modifications around both heterocycles were evaluated with the aim to generate new promising series of benzo[ d ]imidazoles and benzo[ b ]thiophenes derivatives displaying high CB2 selectivity and low toxicity. [ABSTRACT FROM AUTHOR]

In order to well understand the chemical-biological interactions governing their activities toward HIV protease activity, QSAR models of 34 cyclic-urea derivatives with inhibitory HIV were developed. The quantitative structure activity relationship (QSAR) model was built by using comparative molecular similarity indices analysis (CoMSIA) technique. And the best CoMSIA model has r cv 2 , r ncv 2 values of 0.586 and 0.931 for cross-validated and non-cross-validated. The predictive ability of CoMSIA model was further validated by a test set of 7 compounds, giving r pred 2 value of 0.973. Docking studies were used to find the actual conformations of chemicals in active site of HIV protease, as well as the binding mode pattern to the binding site in protease enzyme. The information provided by 3D-QSAR model and molecular docking may lead to a better understanding of the structural requirements of 34 cyclic-urea derivatives and help to design potential anti-HIV protease molecules. [ABSTRACT FROM AUTHOR]

Acetyl-CoA carboxylases (ACC) have long been recognized as an attractive target for metabolic syndrome because of its indispensable role in the regulation of fatty acid metabolism in most living organisms. Based on the lead compound CP-640186, a series of spiro-compounds of benzothiazole derivatives have been identified as ACC inhibitors, which displayed high ACC inhibitor activities and good metabolic stability. Nevertheless, no quantitative structure-activity relationship study has been developed for this kind of ACC inhibitors. In order to evaluate the correlation between changes on structures and variation on biological activity, three-dimensional quantitative structure-activity relationship analysis was employed. Satisfactory results were obtained after performing a leave-one-out cross-validation study with q and r values of 0.625 and 0.927 by the comparative molecular field analysis model, 0.779 and 0.937 by the comparative molecular similarity indices analysis model, respectively. The predictive ability of the models was validated using external validation test set. The contour map analysis of comparative molecular field analysis and comparative molecular similarity indices analysis models indicated that electropositive and bulky groups substituted at the R position of carbamido group, and hydrophilic groups substituted at the phenyl ring were favorable for the inhibitory activity. Furthermore, FlexX docking was employed to investigate the binding mode between human ACC1 and its inhibitors and to validate the three-dimensional quantitative structure-activity relationship models. As a result, based on the results of three-dimensional quantitative structure-activity relationship and FlexX docking, a series of ACC inhibitors with higher predictive activities have been designed. This work might provide valuable information in further optimization of human ACC inhibitors. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) has been identified as a main cause of hospitalisation in infants and children. To date, the current therapeutic arsenal is limited to ribavirin and palivizumab with variable efficacy. In this work, starting from a number of in-house series of previously described anti-RSV agents based on the benzimidazole scaffold, with the aim at gaining a better understanding of the related chemical features involved in potency and safety profiles, we applied a computational study including two focussed comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The results allowed us to derive useful suggestions for the design of derivatives and also to set up statistical models predicting the potency and selectivity index (SI = CC50/EC50) of any new analogue prior to synthesis. Accordingly, here, we discuss preliminary results obtained through the applied exhaustive QSAR analyses, leading to design and synthesise more effective anti-RSV agents. [ABSTRACT FROM PUBLISHER]

The 5-hydroxytryptamine (5-HT1A) receptors represent an attractive target in drug discovery. In particular, 5-HT1Aagonists and partial agonists are deeply investigated for their potential role in the treatment of anxiety, depression, ischaemic brain disorder and more recently, of pain. On the other hand, 5-HT1Aantagonists have been revealed promising compounds in cognition disorders and, lately, in cancer. Thus, the discovery of 5HT1Aligands is nowadays an appealing research activity in medicinal chemistry. In this work, Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) were applied on an in-house library of 5-HT1Aligands bearing different chemical scaffolds in order to elucidate their affinity and selectivity for the target.Following this procedure, a number of structural modifications have been drawn for the development of much more effective 5-HT1AR ligands. [ABSTRACT FROM AUTHOR]

• 1,4-Dihydropyrimidines are usually synthesized from Biginelli reaction. • A series of novel Biginelli-1,4-dihydropyrimidines are rationally designed and synthesized. • Screened against MCF-7 breast cancer cells for their anti-cancer activity by measuring the cytotoxicity. • Dihydropyrimidines exhibited weak to significant cytotoxicity. • Most potent compound (compound 14) is found to inhibit EGFR and HER2 • 3D-QSAR studies were executed to elucidate structure activity relationships in a 3D grid space. • Identified compound 14 to investigate further for its anticancer activity. 1,4-Dihydropyrimidines are usually synthesized from Biginelli reaction which are well known for their anti-cancer activity. A series of novel Biginelli-1,4-dihydropyrimidines are rationally designed, synthesized, purified, analyzed by IR, NMR, Mass spectrometry and screened against MCF-7 breast cancer cells for their anti-cancer activity by measuring the cytotoxicity. Dihydropyrimidines exhibited weak to significant cytotoxicity proportionate to their anti-cancer activity. 14, 7 and 5 have exhibited potent cytotoxicity amongst the screened 33 dihydropyrimidines. Most potent compound 14 is further tested for inhibition of EGFR (epidermal growth factor receptor) and HER2 (human epidermal growth factor receptor 2) expression at 2 different concentrations by taking lapatinib as standard in flow cytometry. 42.02% and 36.45% of cells expressing EGFR and HER2 were inhibited at 500nM/L concentration. Furthermore, 3D-QSAR studies were executed to elucidate structure activity relationships in a 3D grid space by plotting experimental vs predicted cytotoxic activities. [Display omitted] [ABSTRACT FROM AUTHOR]

Aurora A kinase is involved in the inactivation of apoptosis leading to ovarian, breast, colon, and pancreatic cancers. Inhibitors of Aurora A kinase promote aberrant mitosis resulting in arrest at a pseudo G1 state to induce mitotic catastrophe, ultimately leading to apoptosis. In this study, ligand-based and docking-based three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses of imidazole and thiazolidine derivatives as potential Aurora A kinase inhibitors were performed. The results provided highly reliable and predictive 3D-QSAR comparative molecular similarity index analysis (CoMSIA) models with a cross-validated q value of 0.768, non-cross-validated r value of 0.983, and predictive coefficient $${\text{r}}_{\text{pred}}^{2}$$ value of 0.978. CoMSIA contour maps suggested that the NH and benzyl hydroxy groups in R, and the CO group in the thiazolidine ring and pyridine ring were important components for biological activity. The maps also suggest that the introduction of hydroxy groups at C of the imino-phenyl ring, C in the pyridine ring, or the substitution of the imino-phenyl ring for the imino-2-pyridine ring could be applied to enhance biological activity. [ABSTRACT FROM AUTHOR]