QSAR Studies Research Articles

QSAR and molecular docking studies on a series of spirocyclic BACE-1 inhibitors

QSAR and molecular docking studies on a series of spirocyclic BACE-1 inhibitors

Design, Synthesis, and Biological Evaluation of New Azulene-Containing Chalcones.

Azulene-containing chalcones have been synthesized via Claisen–Schmidt condensation reaction. Their chemical structure has been established by spectroscopic methods where the 1H-NMR spectra suggested that the title chalcones were geometrically pure and configured trans (J = 15 Hz). The influence of functional groups from azulene-containing chalcones on the biological activity of the 2-propen-1-one unit was investigated for the first time. This study presents optical and fluorescent investigations, QSAR studies, and biological activity of 10 novel compounds. These chalcones were evaluated for their antimicrobial activity against Gram-positive and Gram-negative bacteria. The results revealed that most of the synthesized compounds showed inhibition against Gram-negative microorganisms, independent of the substitution of azulene scaffold. Instead, all azulene-containing chalcones exhibited good antifungal activity against Candida parapsilosis, with MIC values ranging between 0.156 and 0.312 mg/mL. The most active compound was chalcone containing azulene moieties on both sides of the 2-propene-1-one bond, exhibiting good activity against both bacteria-type strains and good antifungal activity. This antifungal activity combined with low toxicity makes azulene-containing chalcones a new class of bioorganic compounds.

QSAR modeling, molecular docking, ADMET prediction and molecular dynamics simulations of some 6-arylquinazolin-4-amine derivatives as DYRK1A inhibitors

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a protein kinase with diverse functions in neuronal development and adult brain physiology. QSAR study was performed for a diverse set of thirty-three6-arylquinazolin-4-amine derivatives as DYRK1A inhibitors. The QSAR model with HOMO, LUMO, qCsub, SAG and MW descriptors showed satisfactory internal and external validation parameters (Rtrain2=0.867,Radj2=0.831, QLOO2= 0.755,F=24.682 andRpred2 =0.856). The excellent statistical results obtained for the developed model, strongly suggest that the model is reasonable for the prediction of the activity of new inhibitors. Therefore, we have designed several new potent DYRK1A inhibitors and validated their inhibitory activity by molecular docking methods using Autodock tools. Based in silico analysis, two novel compounds N2 and N11have been designed, which they have been identified hydrophobic and hydrogen bonds, with the binding pockets of active site4YLJ. Furthermore, the two newly designed compounds exhibited good ADMET properties, their molecular dynamics studies have shown a favorable energetic state and dynamic stability, characterized by root mean square deviation (RMSD), root mean square fluctuation (RMSF) and hydrogen bond. The outcomes of this study can be used to show the interest of DYRK1A inhibition for Alzheimer treatment.

Synthesis, Biological Evaluation, 2D-QSAR, and Molecular Simulation Studies of Dihydropyrimidinone Derivatives as Alkaline Phosphatase Inhibitors.

The presence of alkaline phosphatases has been observed in several species and has been known to play a crucial role in various biological functions. Higher expressions of alkaline phosphatase have been found in several multifactorial disorders and cancer patients, which has led it to be an interesting target for drug discovery. A strong structural similarity exists between intestinal alkaline phosphatases (IAPs) and tissue-nonspecific alkaline phosphatases (TNAPs), which has led to the discovery of only a few selective inhibitors. Therefore, a series of 22 derivatives of 6-(chloromethyl)-4-(4-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1) and ethyl 6-(chloromethyl)-4-(2-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2) were synthesized to evaluate the anticancer potential of these compounds against breast cancer. The compounds were characterized through spectral and elemental analyses. The inhibitory effect of dihydropyrimidinone derivatives on alkaline phosphatases was evaluated using the calf alkaline phosphatase assay. The antioxidant activity of these compounds was performed to study the radical scavenging effect. In silico molecular docking and molecular dynamic simulations were performed to elucidate the binding mode of active compounds. Moreover, the two-dimensional qualitative-structure–activity relationship (2D-QSAR) was performed to study the structural requirements for enzyme inhibition. The calf alkaline phosphatase inhibitory assay revealed significant inhibition of the enzyme by compound 4d with IC50 1.27 μM at 0.1 mM concentration as compared to standard KH2PO4 having IC50 2.80 μM. The compounds 4f, 4e, and 4i also showed very good inhibition with IC50 values of 2.502, 2.943, and 2.132 μM, respectively, at the same concentration. The antioxidant assay revealed efficient radical scavenging activity of compounds 4f, 4e, and 4g at 100 μg/mL with IC50 values of 0.48, 0.61, and 0.75 μg/mL, respectively. The molecular docking and simulation studies revealed efficient binding of active compounds in the active binding site of the target enzyme. The final QSAR equation revealed good predictivity and statistical validation having R2 = 0.958 and Q2 = 0.903, respectively, for the generated model. The compound 4d showed the highest inhibitory activity with stable binding modes acting as a future lead for identifying alkaline phosphatase inhibitors. The molecular simulations suggested the stable binding of this compound, and the QSAR studies revealed the importance of autocorrelated descriptors in the inhibition of alkaline phosphatase. The investigated compounds may serve as potential pharmacophores for potent and selective alkaline phosphatase inhibitors. We intend to further investigate the biological activities of these compounds as alkaline phosphatase inhibitors.

Synthesis, molecular modelling and QSAR study of new N-phenylacetamide-2-oxoindole benzensulfonamide conjugates as carbonic anhydrase inhibitors with antiproliferative activity

In continuation of our previous studies to optimise potent carbonic anhydrase inhibitors, two new series of isatin N-phenylacetamide based sulphonamides were synthesised and screened for their human (h) carbonic anhydrase (EC 4.2.1.1) inhibitory activities against four isoforms hCA I, hCA II, hCA IX and hCA XII. The indole-2,3-dione derivative 2h showed the most effective inhibition profile against hCAI and hCA II (KI = 45.10, 5.87 nM) compared to acetazolamide (AAZ) as standard inhibitor. Moreover, 2h showed appreciable inhibition activity against the tumour-associated hCA XII, similar to AAZ showing KI of 7.91 and 5.70 nM, respectively. The analogs 3c and 3d showed good cytotoxicity effects, and 3c revealed promising selectivity towards lung cell line A549. Molecular docking was carried out for 2h and 3c to predict their binding conformations and affinities towards the hCA I, II, IX and XII isoforms.

Efficient Synthesis of Novel N-[4-Methyl-3-(4-(5-phenyl-1,3,4-oxadiazol-2- yl)phenyl)thiazol-2(3H)-ylidene]benzamide Hybrid Ring System as Potential Antibacterial Agents.

Heterocyclic compounds display versatile biological applications, so the aim of this paper was to prepare biologically important heterocycles with enhanced bacterial resistance and to evaluate for their various structural features that are responsible for their biological properties. The objective was to synthesize bacterial resistance compounds with enhanced antibacterial properties. Ester moiety containing thiazole ring was converted into its hydrazide derivatives. These heterocyclic derivatives were cyclized into another ring oxadiazole; hence a hybrid ring system of two biologically active rings was prepared. All the synthesized compounds were characterized by spectroscopic techniques and were screened for their antibacterial potential; they possess significant antibacterial activities. New hybrid heterocyclic ring systems were synthesized by cyclization of hydrazide derivatives by adopting two step strategy in good yields. All the synthesized compounds were evaluated for their antioxidant activities; they showed moderate to significant activities. QSAR and Molecular docking studies were performed to determine the mode of interaction. Experimental and computational data is in accordance with the determined antibacterial activities.

Spectral characterization and biological studies of some ternary complexes with molecular docking investigations against MERS and SARS type coronaviruses

ABSTRACT. A series of ternary complexes with a Schiff base (HL1) derived from 2-hydrazinobenzimidazole and o-hydroxybenzophenone (primary ligand) have been prepared. Here, 1,10-phenanthroline acts as secondary ligand (L2). These metal complexes were investigated by UV-Vis, IR, 1H NMR and thermal techniques. The spectral data confirmed tridentate nature of the SB ligand with NNO type coordination, whereas the secondary ligand L2 (1,10-phenanthroline) coordinated through its two nitrogen atoms (NN type). These compounds possess distorted octahedral geometry. Moreover, these compounds were screened against B. subtilis and E. coli to evaluate their antibacterial activity. In addition, molecular docking studies were performed against MERS-CoV and SARS-CoV-2 main protease (Mpro). Moreover, DFT calculations and QSAR studies of the SB ligand were also performed.
 
 KEY WORDS: Ternary complexes, Spectral, Antibacterial, DFT, QSAR, Molecular docking studies
 
 Bull. Chem. Soc. Ethiop. 2021, 35(3), 525-535.
 DOI: https://dx.doi.org/10.4314/bcse.v35i3.5

Molecular Docking and QSAR Studies for Modeling the Inhibitory Activity of Pyrazole-benzimidazolone Hybrids as Novel Inhibitors of Human 4-hydroxyphenylpyruvate dioxygenase Against Type I Tyrosinemia Disease

Pyrazole-benzimidazolone is a novel inhibitor of human 4-Hydroxyphenylpyruvate dioxygenase of the HPPD receptor. To analyze this inhibitory activity, a QSAR study was performed using 33 compounds. The MLR multiple linear regression method and the NN neural network were used to establish the predicted model. This model was validated by the external validation method. The molecular electronic descriptors were calculated by the DFT method. This study shows that the activity of the compounds is strongly correlated with the five descriptors selected by the MLR method. The correlation coefficients calculated by MLR and then by NN are R =0.878 and R =0.978; they allow us to evaluate the proposed quantitative model. The latter allowed us to predict the activity of new HPPD receptor inhibitors and to show the good predictive competence of the established QSAR model. Based on these results, we performed docking in the active site of HPPD protein with the most active compound (12), and we deduced that this compound specifically interacts with are GLN 307, ASN 423, and PHE 392 at the HPPD protein binding pocket; thus, it showed additional interactions with VAL 228, PRO 280, SER 267, LEU 265, LYS 421, GLN 379, GLY 420, and LEU 368, This interaction is similar to that of NTBC with the active site.

QSAR studies of BBR analogues against coxsackievirus B1

BackgroundCoxsackievirus group B (CVBs) are common enteroviruses associated with several diseases from etiologically to inflammatory cardiomyopathies and constitute a severe cause of mortality in newborn resulting in severe meningitis, fulminant infection, myocarditis, and encephalitis. While Berberian (BBR) is an effective antivirus and possesses potentials of suppressing CVB replication, Zeng et al. explored a structural modification of BBR by incorporating a substituted primary amine enhance antiviral potency and safety. Based on data set from Zeng et al., we attempted to propose a QSAR model that can predict the bioactivity of unknown compounds as anti-CVB1.ResultsAmong many descriptors, four were selected using the Genetic Functional Approximation (GFA). Internal and external validation was carried out on data set using statistical parameters. The QSAR model was seen to meet the minimum requirement with Lack of fit = 0.068744, R2 0.897, Adjusted R2 = 0.8627, cross-validated R2 = 0.76169, R2 predicted = 0.68.ConclusionThe predictive ability of the model was found to be satisfactory and could be used for designing a similar group of compounds.

The investigation of influencing factors on the degradation of sulfonamide antibiotics in iron-impregnated biochar-activated urea-hydrogen peroxide system: A QSAR study

Iron-impregnated biochar-activated urea-hydrogen peroxide (FB-activated UHP) is a potential in-situ technology for simultaneously reducing soil sulfonamide antibiotic contaminants and improving soil fertility. To better understand the degradation of sulfonamide antibiotics by FB-activated UHP, a two-dimensional quantitative structure-activity relationship (2D-QSAR) model based on quantum chemical parameters and a three-dimensional QSAR (3D-QSAR) model based on molecular force field were developed to investigate the factors influencing the removal efficiencies (Re%). The optimal 2D-QSAR model was Re%= 0.858–8.930 E-5 EB3LYP-0.175 f(+)x with the evaluation indices of R2= 0.732, q2= 0.571, and Qext2= 0.673. The given 2D-QSAR model indicated that the molecular size (EB3LYP) and Fukui index with respect to nucleophilic attack (f(+)) were intrinsic factors influencing Re%. Three degradation pathways were subsequently proposed based on the f(+) distribution. Compared to the 2D-QSAR model, the developed 3D-QSAR model exhibited a better predictive ability, with the evaluation indices of R2= 0.989, q2= 0.696, and SEE= 0.001. The analysis of field contribution rates suggested that electrostatic field (48.2%), hydrophobic field (25.3%), and hydrogen-bond acceptor field (12.7%) were the main factors influencing Re%. These findings generated critical information for evaluating the degradation mechanisms/rules and provided theoretical bases for initially estimating the Re% of sulfonamide antibiotics undergoing FB-activated UHP process.

MOLECULAR MODELING STUDIES OF BENZIMIDAZOLYL-CHALCONES AS ANTILEISHMANIAL AGENTS USING QSAR, DOCKING, ADME AND MOLECULAR DYNAMICS STUDIES

Introduction: Present leishmaniasis treatment regimen has many limitations including severe adverse effects, toxicity, and Leishmania strains resistance. In the present study, the objective is to perform QSAR, molecular docking and ADME prediction studies on benzimidazolylchalcones in order to select an antileishmanial drug candidate.Materials & methods: QSAR models were performed on 12 benzimidazolylchalcones with antileishmanial activities against promastigote strains of L. donovani. Binding free energy calculations were performed using MM-GBSA to assess the affinity of the ligands for the proteins. In addition, the three most active compounds (4a-c, IC50 <1-μM) were docked with the protein phosphodiesterase B1 (PDB ID: 2JK6).Results and Discussion: The optimum model has squared correlation coefficient (R2) of 0.983, and leave-one-out (LOO) cross-validation coefficient (Q2CV) value of 0.942. The number of descriptors involved in the model is acceptable (R2 - Q2CV = 0.041), which confirms the model’s stability and validates the developed model’s predictive power. Docking studies revealed that the best compound 4c formed hydrogen bond with SER 464, pi-cation contact with LYS 61 and hydrophobic interactions with LEU 62, TYR 64 and LEU72 of the active site of L. donovani phosphodiesterase B1. ADME properties results showed that all three molecules have good pharmacokinetic properties.Conclusion: Finally, molecular dynamics simulation studies at 30 ns revealed stable interactions with the 2JK6 protein. This study validates the choice of the ortho-chlorinated derivative of benzimidazolylchalcones as the lead compound for developing new derivatives with optimized antileishmanial properties.

Novel benzothiazole-based dual VEGFR-2/EGFR inhibitors targeting breast and liver cancers: Synthesis, cytotoxic activity, QSAR and molecular docking studies

A novel series of benzothiazole-based derivatives linked to various amino acids and their corresponding ethyl ester analogues were prepared and were initially evaluated for their anticancer activity againstMCF-7 and HepG-2 and were further assessed as VEGFR-2 inhibitors. All the newly synthesized benzothiazole derivatives showed promising cytotoxic activities against the tested cell lines. Derivatives exhibited potent cytotoxic and VEGFR-2 inhibitory activities were then evaluated further as anticancer agents against the resistant MDA-MB-231 and as EGFR inhibitors. The carboxylic acid derivatives 10–12 and their ester analogues 21–23 displayed the highest anticancer activities with IC50 of 0.73–0.89 µM, against MCF-7 and IC50 of 2.54–2.80 µM, against HepG-2; compared to doxorubicin (IC50 = 1.13 and 2.75 µM, respectively); also they showed safety towards the normal cell line, the ethyl ester derivatives 21–23 showed a potent activity against the resistant MDA-MB-231 cell line with IC50 of 5.45–7.28 µM, relative to doxorubicin (IC50 = 7.46 µM) surpassing their carboxylic acid analogues 10–12 (IC50 of 8.88–11.02 µM). Furthermore, the promising derivatives 10–12 and 21–23 displayed promising VEGFR-2 inhibitory activity (IC50 = 0.15–0.19 µM) comparable to that of sorafenib (IC50 = 0.12 µM). Against EGFR, the ethyl ester derivatives 21–23 showed superior inhibitory activity relative to the used reference standard, erlotinib, with IC50 of 0.11–0.16 vs. 0.18 µM, respectively. The QSAR study revealed that the molecular bulkiness and molecular partial charge distribution govern the kinase inhibition potency in this series. Furthermore, the molecular docking study in VEGFR-2 active site showed that the novel synthesized benzothiazole derivatives adopted the common binding pattern of type II PK inhibitors.

Molecular insights of oxadiazole benzene sulfonamides as human carbonic anhydrase IX inhibitors: Combined molecular docking, molecular dynamics, and 3D QSAR studies

α - CA IX isozyme over-expression in hypoxic environment becomes an attractive target for the design of inhibitors targeting cancer particularly, tumor progression and invasion. AimIn the process of designing new scaffolds, oxadiazole benzene sulfonamide leads were explored and evaluated for the selective inhibition of tumor-associated hCA IX. The chemical dataset compounds with human carbonic anhydrase IX inhibition values were subjected to QSAR study for generating validated models. ResultsThe best statistically validated model with three descriptors MATSe1, GATSm6 and MoRSEM15 was utilized for designing compounds with improved bioactivity. Further new molecules were taken over for the molecular docking studies and the best lead for molecular dynamics simulation and binding free energy studies. The outcome of the QSAR and molecular docking studies resulted in the development of lead molecules. Among the designed compounds two molecules 35a and 38a were further studied for molecular interactions and observations led to the residues of active site region involving both hydrophilic and hydrophobic interactions. ConclusionMolecular dynamics simulation studies for the lead molecule 38a in comparison to the reference provided useful structural insights. Further, fluctuations of the residues, H-bond profiles and stability analysis by RMSD, RMSF, RoG were studied. In addition, MM-PBSA and MM-GBSA also affirms the docking results. We propose the designed compound 38a as the best theoretical lead which may further be experimentally studied for selective inhibition.

Molecular structural investigations of quinoxaline derivatives through 3D-QSAR, molecular docking, ADME prediction and pharmacophore modeling studies for the search of novel antimalarial agent

In the present article, a dataset of 63 quinoxaline derivatives were taken for antimalarial activity and pharmacophore were developed. Atom based method was used to develop a three dimensional quantitative structure activity relationship (3D-QSAR) model. On comparison of all statistical parameters, model AHRRR23 was found to be the most effective and predictive QSAR model as it satisfied all statistical parameters of a good model. The model AHRRR23 showed an adequate R2 value for the training set 0.9446, good predictive power with Q2 of 0.6409, good F- value, low SD 0.1218 value and outstanding Pearson-R values and low RMSE 0.2779 values of the model. The docking studies also gives very good results with good RMSD values. 3D QSAR, docking and ADME studies exhibits that the developed model could be employed as a potential lead for further study as antimalarial drug.

Corrosion Inhibition Studies of 8-Hydroxyquinoline Derivatives for N80 Steel in 1.0 M Hcl Solution: Experimental, Computational Chemistry, and Qsar Studies

Corrosion Inhibition Studies of 8-Hydroxyquinoline Derivatives for N80 Steel in 1.0 M Hcl Solution: Experimental, Computational Chemistry, and Qsar Studies

Computational investigation of Betalain derivatives as natural inhibitor against food borne bacteria

Natural organic pigments such as carotenoids, betalains, anthocyanins, and carminic acid are notably found as safer food preservatives compared to other harmful synthetic chemicals. Due to glycosylation and acylation, betalains exhibit a broad-spectrum antimicrobial functionality with protection against degenerative diseases. Thus, betalains have been investigated as a potential bacterial inhibitor for food preservative applications. Initially, 36 betalain derivatives have been taken for primary screening using molecular docking. Afterward, the top ten ligands are taken for further study and analysis. The results of Prediction of Activity Spectrum of Substances (PASS) assured the antibacterial capabilities of betalains, and Lipinski's rule-of-five ensures the acceptability of the selected ligands as antibacterial inhibitors. The bacterial pathogens, such as C. botulinum (3FIE), E. coli (2ZWK), and S. typhi (3UU2) are selected for molecular docking by these betalain pigments. Furthermore, ADMET investigations and QSAR studies are performed to check insights into the bacterial inhibition process. Most active and common binding sides were observed at GLY159, ASN165, and SER166 for C. botulinum, at ASP8, LYS40, and TRP50 for E. coli; and at ARG37, GLN5, and ARG74 for S. typhi. The present study clearly shows an excellent insight towards the invention of plant-based new organic inhibitors to face the challenges of bacterial-resistant common food preservatives.

Computation method of the Hosoya index of primitive coronoid systems.

Coronoid systems are natural graph representations of coronoid hydrocarbons associated with benzenoid systems, but they differ in that they contain a hole. The Hosoya index of a graph G is defined as the total number of independent edge sets, that are called k-matchings in G. The Hosoya index is a significant molecular descriptor that has an important position in QSAR and QSPR studies. Therefore, the computation of the Hosoya index of various molecular graphs is needed for making progress on investigations. In this paper, a method based on the transfer matrix technique and the Hosoya vector for computing the Hosoya index of arbitrary primitive coronoid systems is presented. Moreover, the presented method is customized for hollow hexagons by using six parameters. As a result, the Hosoya indices of both each arbitrary primitive coronoid system and also each hollow hexagon can be computed by means of a summation of four selected multiplications consisting of presented transfer matrices and two vectors.

A Quantitative Structure Activity Relationship (Qsar) Studies for 2-Oxo-1, 2-Dihydroquinoline-4-Carboxylic Acid Derivatives

A Quantitative Structure Activity Relationship (Qsar) Studies for 2-Oxo-1, 2-Dihydroquinoline-4-Carboxylic Acid Derivatives

Eccentric Harmonic Index for the Cartesian Product of Graphs

Suppose ρ is a simple graph, then its eccentric harmonic index is defined as the sum of the terms 2/ea + eb for the edges vavb, where ea is the eccentricity of the ath vertex of the graph ρ. We symbolize the eccentric harmonic index (EHI) as He = He(ρ). In this article, we determine He for the Cartesian product (CP) of particularly chosen graphs. Lower bounds for He of the CP of the two graphs are established. The formulas of EHI for the Hamming and Hypercube graphs are obtained. These obtained formulas can be used in QSAR and QSPR studies to get a better understanding of their applications in mathematical chemistry.

QSAR Studies of Flavonoids and Isoflavonoids with PTP1B: A Potential Pharmacological Target for the Treatment of Insulin Resistance

This study deals with designing and validating QSAR models generated for 45 flavonoids having PTP1B inhibition properties. Eight molecular descriptors/pharmacophoric features of each flavonoid along with their reported IC50 values against PTP1B were utilized to prepare training sets and generate models. It was developed by employing linear regression to calculate the predicted IC50 values. The generated models were validated using reported IC50 values of test sets. The correlation R2 values were observed to be in the following order, 92.45% (for an increasing hydrogen bond donor), 92.08% (for randomly sorting), 91.85% (for increasing molecular weight), 84.19% (for increasing hydrogen bond acceptor), 64.91% (for increasing TPSA), 53.90% (for increasing number of rotatable bonds) and 52.28% (for increasing log P); signifying the role of these pharmacophoric features while drug designing. Molecular docking of the flavonoids with the PTP1B active site revealed interactions with catalytic site and adjacent loops. The models would be beneficial for further studies for drug designing against PTP1B inhibition and therapeutic implications for treatment of insulin resistance.