CoMSIA Models Research Articles

Studies on molecular mechanism between ACE and inhibitory peptides in different bioactivities by 3D-QSAR and MD simulations

Abstract 3D-QSAR, molecular docking and molecular dynamics (MD) simulations were performed to investigate the mechanism of ACE-inhibitory (ACEi) peptides with tryptophan C-terminal in aqueous solutions. In this work, COMFA (Q2 = 0.85, R2 = 0.993) and COMSIA (Q2 = 0.706, R2 = 0.997) models of di- and tri-peptides were established. Novel tripeptides were predicted by the 3D-QSAR models. Different conformations and interactions between VKW with high activity and GTW with low activity were compared by MD simulation. The results revealed VKW had stronger electrostatic interaction and binding affinity with key residues of ACE. ACE-VKW complex performed more stable than ACE-GTW. Thus, VKW showed a higher activity. Moreover, ACEi tripeptides with Trp C-terminal potentiate the combination with Zn of ACE active pockets.

Investigation of the interactions between flavonoids and human organic anion transporting polypeptide 1B1 using fluorescent substrate and 3D-QSAR analysis

Organic anion transporting polypeptide 1B1 (OATP1B1) is a key hepatic uptake transporter whose inhibition could lead to adverse drug-drug and drug-food interactions. Flavonoids are widely distributed in food and beverages and thus our bodies are frequently exposed to them. Therefore, investigation of the interactions between OATP1B1 and flavonoids could be of great significance. In the present study, 25 common flavonoids were investigated for their interactions with OATP1B1 using the fluorescent substrate 2′,7′-dichlorofluorescein (DCF) and three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis. Kinetic study showed that OATP1B1-mediated DCF uptake exhibited a monophasic saturation kinetics with a Km value of 9.7 ± 2.4 μM. Inhibition assay for flavonoids on OATP1B1-mediated DCF uptake was performed and their IC50 values were determined upon which reliable and predictive CoMFA (q2 = 0.604, r2 = 0.841) and CoMSIA (q2 = 0.534, r2 = 0.807) models were developed. Our experimental and computational results showed that flavonoid aglycones interacted with OATP1B1 much stronger than their glycosides such as 3-O- and 7-O-glycosides as bulky hydrophilic and hydrogen-bond forming substituents at C-3 and C-7 positions on rings A and C were unfavorable for their binding. On the other hand, the presence of hydrogen-bond forming groups on ring B was beneficial as long as the number of hydroxyl groups was not >2. Our results also indicated that flavones usually interacted with OATP1B1 much stronger than their 3-hydroxyflavone counterparts (flavonols). The obtained information and 3D-QSAR models could be useful for elucidating and predicting the interactions between flavonoids and human OATP1B1.

Structural insights for rational design of new PIM-1 kinase inhibitors based on 3,5-disubstituted indole derivatives: An integrative computational approach

Proviral integration Moloney virus (PIM) 1, 2, and 3 kinases are a family of constitutively active serine/threonine kinases that are involved in a number of signaling pathways important to cancer cells. Their overexpression in a variety of human hematopoietic malignancies and solid tumors suggest that inhibition of PIM signaling could provide patients with therapeutic benefit. In this study, a series of 3,5-disubstituted indole derivatives have been systematically studied using three-dimensional quantitative structure-activity relationship (3D−QSAR) analysis, molecular docking simulation, and partial least-squares (PLS) analysis methods to explore the influence of the structural characteristics on the inhibitory activity and use them to propose novel bioactive molecules. The comparative molecular field and comparative molecular similarity indices analyses (CoMFA and CoMSIA) models exhibited a good correlation between the predicted and experimental activities with excellent predictive capability and yielded statistically reliable value (CoMFA: Q2 = 0.535, R2 = 0.987, r2pred = 0.909; CoMSIA: Q2 = 0.785, R2 = 0.989, r2pred = 0.969). Based on the CoMFA and CoMSIA models and docking results, ten novel potent PIM-1 inhibitors (N1–N10) have been designed and the molecular models have validated their inhibitory activities. These results provided strong theoretical guidance for the development of novel PIM-1 inhibitors.

Synthesis, biological activities, and 3D-QSAR studies of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfonohydrazide moiety

To discover a novel lead structure for antiphytopathogenic fungus agent, a series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfonohydrazide moiety were designed and synthesized. They were determined by melting points, 1H NMR, 13C NMR, and elemental analysis (EA). The biological activity results revealed that these title compounds possessed antifungal and insecticidal activities. Some title compounds against Alternaria solani, Physalospora piricola, Cercospora arachidicola, Phytophthora capsici, Fusarium graminearum, and Sclerotinia sclerotiorum displayed moderate to good antifungal activities at 50 mg/L, especially, compounds 6b and 6p displayed good and broad-spectrum antifungal activities. The structure activity relationships were discussed. A 3D-QSAR model was established based on the antifungal activity against Phytophthora capsici, indicating that electrostatic and hydrophobic fields were the two most significant factors for antifungal activity. Hence, structure optimization based on the CoMSIA model was performed to find compound 6p with excellent activity against Phytophthora capsici, and the EC50 values of compound 6p were comparable to those of chlorothalonil. Furthermore, the insecticidal activity of compound 6p against Culex pipiens larvae at 1 mg/L was considerable to that of chlorantraniliprole. Therefore, compound 6p can be used as a novel lead structure for antiphytopathogenic fungus and insecticidal agent development.

Synergy and isosterism design of a phosphorus-free lubricating additive

Thirty-one hydrazides were selected as isosteres and other analogs when five phosphates were used as templates by an isosteric exchange from phosphate group (PO4) to hydrazide group (CONHN). Their tribological properties of the lubricant modified with 1% hydrazide or phosphate additives were tested under 98 N load in three base oils, respectively. About 40% of the isosteres showed an acceptable deviation of ±5% relative to the template. The phosphate template molecules and hydrazide isosteres have better tribological properties in triisodecyl trimellitate than trimethylolpropane trioleate or di(2-ethylhexyl) adipate. Especially, most of the other hydrazide analogs have better antiwear property because of the same CONHN group as the isostere. CoMFA and CoMSIA models were used to discuss the dependency of molecular structure. The models show that the higher the structural similarity between the base oil and the additive, the more synergy the molecular force field in a lubricant, which may ameliorate the antiwear or friction-reduction properties. Surface analysis of the worn disc specimen also shows similarity between a template and an isostere by Scanning Electron Microscopy, EDS, and Raman spectra.

(R)-2-Phenyl-4,5-Dihydrothiazole-4-Carboxamide Derivatives Containing a Diacylhydrazine Group: Synthesis, Biological Evaluation, and SARs.

A series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a diacylhydrazine moiety were designed and synthesized. Their structures were confirmed by melting points, 1H NMR, 13C NMR, and elemental analysis (EA). Their antifungal and insecticidal activities were evaluated. The antifungal activity result indicated that most title compounds against Cercospora arachidicola, Alternaria solani, Phytophthora capsici, and Physalospora piricola exhibited apparent antifungal activities at 50 mg/L, and better than chlorothalonil or carbendazim. The EC50 values of (R)-N’-benzoyl-2-(4-chlorophenyl)-4,5-dihydrothiazole-4-carbohydrazide (I-5) against six tested phytopathogenic fungi were comparable to those of chlorothalonil. The CoMSIA model showed that a proper hydrophilic group in the R1 position, as well as a proper hydrophilic and electron-donating group in the R2 position, could improve the antifungal activity against Physalospora piricola, which contributed to the further optimization of the structures. Meanwhile, most title compounds displayed good insecticidal activities, especially compound (R)-N’-(4-nitrobenzoyl)-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carbohydrazide (III-3). The insecticidal mechanism results indicated that compound III-3 can serve as effective insect Ca2+ level modulators by disrupting the cellular calcium homeostasis in Mythimna separata.

Two-dimensional and Three-dimensional quantitative structure-activity relationship models for the degradation of organophosphate flame retardants during supercritical Water oxidation

Organophosphate flame retardants (OPFRs) have been increasingly utilized as flame retardants in various fields due to the phasing out of polybrominated diphenyl ethers. To achieve a better understanding of the degradation of OPFRs undergoing supercritical water oxidation (SCWO) process, two-dimensional and three-dimensional quantitative structure-activity relationship (2D-QSAR and 3D-QSAR) models were established to investigate the factors influencing the total carbon degradation rates (kTOC). Results of the QSAR models demonstrated reliable results to estimate the kTOC values, but varied in the influencing factors. Two distinct degradation mechanisms were subsequently proposed based on the distribution of LUMO in molecules for the 2D-QSAR model. CoMFA and CoMSIA methods were applied to develop the 3D-QSAR models. Steric fields were observed to influence kTOC values more than electrostatic fields in the CoMFA model with the contribution rates of 87.2% and 12.8%, respectively. In the CoMSIA model, influence on kTOC values varies between different types of fields with the hydrophobic field being the most influential at 62.1%, followed by the steric field at 25.7% and then the electrostatic field at 10.8%. Results from this study generated critical knowledge of influencing factors on OPFRs degradation and yielded theoretical basis for estimating removal behaviors of OPFRs undergoing SCWO process.

Design, synthesis and 3D-QSAR analysis of novel thiopyranopyrimidine derivatives as potential antitumor agents inhibiting A549 and Hela cancer cells

Four series of thiopyranopyrimidine AZD9291 derivatives containing acrylamide structure were designed, synthesized and evaluated for their antiproliferative activity against A549 and Hela cancer cells. Most of the compounds exhibited excellent antiproliferative activity against A549 cells. Moreover, the compounds with indole ring fluorine substituted exhibited better antiproliferative activity against Hela cells. The most promising compound 23g exhibited excellent enzymatic inhibitory activity and selectivity for EGFRL858R/T790M double mutations. The IC50 value against EGFRL858R/T790M kinase was 16 nM. The compound 23g inhibits selectively against the mutated form of EGFR, with the selectivity more than 125-fold. Furthermore, compound 23g also inhibited A549 cells, Hela cells and H1975 cells proliferation at a low concentration, and the IC50 values were 0.057 μM, 0.104 μM and 0.916 μM, respectively. To further investigate the QSARs of thiopyranopyrimidine derivatives, the CoMFA (q [2] = 0.765, r2 = 0.965) and CoMSIA (q [2] = 0.875, r2 = 0.956) models on Hela cancer cells were established. The generated 3D-QSAR model was validated to be reliable and can be used for further design and optimization of novel and selective EGFR inhibitors.

In silico study directed towards identification of the key structural features of GyrB inhibitors targeting MTB DNA gyrase: HQSAR, CoMSIA and molecular dynamics simulations

ABSTRACTMycobacterium tuberculosis DNA gyrase subunit B (GyrB) has been identified as a promising target for rational drug design against fluoroquinolone drug-resistant tuberculosis. In this study, we attempted to identify the key structural feature for highly potent GyrB inhibitors through 2D-QSAR using HQSAR, 3D-QSAR using CoMSIA and molecular dynamics (MD) simulations approaches on a series of thiazole urea core derivatives. The best HQSAR and CoMSIA models based on IC50 and MIC displayed the structural basis required for good activity against both GyrB enzyme and mycobacterial cell. MD simulations and binding free energy analysis using MM-GBSA and waterswap calculations revealed that the urea core of inhibitors has the strongest interaction with Asp79 via hydrogen bond interactions. In addition, cation-pi interaction and hydrophobic interactions of the R2 substituent with Arg82 and Arg141 help to enhance the binding affinity in the GyrB ATPase binding site. Thus, the present study provides crucial structural features and a structural concept for rational design of novel DNA gyrase inhibitors with improved biological activities against both enzyme and mycobacterial cell, and with good pharmacokinetic properties and drug safety profiles.

QSAR analysis of coumarin-based benzamides as histone deacetylase inhibitors using CoMFA, CoMSIA and HQSAR methods

Histone deacetylases (HDACs) as the promising therapeutic targets for the treatment of cancer and other diseases, modify chromatin structure and contribute to aberrant gene expression in cancer. Inhibition of HDACs is emerging as an important strategy in human cancer therapy and HDAC inhibitors (HDACIs) enable histone to maintain a high degree of acetylation. In this work, molecular modeling studies, including CoMFA, CoMFA-RF, CoMSIA and HQSAR and molecular docking were performed on a series of coumarin-based benzamides as HDAC inhibitors. The statistical qualities of generated models were justified by internal and external validation, i.e., cross-validated correlation coefficient (q2), non-cross-validated correlation coefficient (rncv2) and predicted correlation coefficient (rpred2), respectively. The CoMFA (q2, 0.728; rncv2, 0.982; rpred2, 0.685), CoMFA-RF (q2, 0.764; rncv2, 0.960; rpred2, 0.552), CoMSIA (q2, 0.671; rncv2, 0.977; rpred2, 0.721) and HQSAR models (q2, 0.811; rncv2, 0.986; rpred2, 0.613) for training and test set of HDAC inhibition of HCT116 cell line yielded significant statistical results. Therefore, these QSAR models were excellent, robust and had better predictive capability. Contour maps of the QSAR models were generated and validated by molecular docking study. The final QSAR models could be useful for the design and development of novel potent HDAC inhibitors in cancer treatment. The amido and amine groups of benzamide part as scaffold and the bulk groups as a hydrophobic part were key factors to improve inhibitory activity of HDACIs.

3D QSAR Modeling and Molecular Docking Studies on a series of quinolone-triazole derivatives as antibacterial agents

A serie of seventeen quinolone- triazoles derivatives as antibacterial agents were studied based on the combination of 3D-QSAR and surflex-docking. The CoMFA and CoMSIA models were carried out using 13 compounds in the training set and 4 compounds in the test set give high R 2 values of 0.98 for CoMFA and 0.976 for CoMSIA, that latter present high Q 2 value of 0.72, while CoMFA present a Q 2 value of 0.71. Based on these statistics, we proposed new compounds with high predicted activities, Surflex-docking revealed the important interactions between the ligand and receptor. Therefore, it confirmed the stability of predicted molecules in the receptor with PDB: 3AIE.

Homology modeling and 3D–QSAR study of benzhydrylpiperazine δ opioid receptor agonists

The binding affinity of a series of benzhydrylpiperazine δ opioid receptor agonists were pooled and evaluated by using 3D-QSAR and homology modeling/molecular docking methods. Ligand-based CoMFA and CoMSIA 3D-QSAR analyses with 46 compounds were performed on benzhydrylpiperazine analogues by taking the most active compound BW373U86 as the template. The models were generated successfully with q2 value of 0.508 and r2 value of 0.964 for CoMFA, and q2 value of 0.530 and r2 value of 0.927 for CoMSIA. The predictive capabilities of the two models were validated on the test set with R2pred value of 0.720 and 0.814, respectively. The CoMSIA model appeared to work better in this case. A homology model of active form of δ opioid receptor was established by Swiss-Model using a reported crystal structure of active μ opioid receptor as a template, and was further optimized using nanosecond scale molecular dynamics simulation. The most active compound BW373U86 was docked to the active site of δ opioid receptor and the lowest energy binding pose was then used to identify binding residues such as s Gln105, Lys108, Leu125, Asp128, Tyr129, Leu200, Met132, Met199, Lys214, Trp274, Ile277, Ile304 and Tyr308. The docking and 3D-QSAR results showed that hydrogen bond and hydrophobic interactions played major roles in ligand-receptor interactions. Our results highlight that an approach combining structure-based homology modeling/molecular docking and ligand-based 3D-QSAR methods could be useful in designing of new opioid receptor agonists.

Designing of novel ERRγ inverse agonists by molecular modeling studies of docking and 3D-QSAR on hydroxytamoxifen derivatives

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.

Insights into the c-Jun N-terminal kinase 3 (JNK3) inhibitors: CoMFA, CoMSIA analyses and molecular docking studies

JNK3, a protein kinase of the MAPK family that is potently activated by a variety of environmental stress and pro-inflammatory cytokines, has been recognized as an important therapeutic target for several neurodegenerative diseases. However, due to the long development cycle and the cost of R&D, no related drugs have been released. By applying the CoMFA and CoMSIA methods, QSAR models that explore the structure-activity relationship of the JNK3 inhibitors are established and validated, the parameters are satisfactory (q2 = 0.774, r2 = 0.991 for CoMFA model and q2 = 0.666, r2 = 0.990 for CoMSIA model) and base on which a series of novel molecules are designed. Molecular docking is conducted to verify the potential of the new compounds, the results shows promising activity. We speculated that the series of compounds S1–S11 might have some therapeutic activity in the c-jnk3 pathway, particularly the “S8” may prove to be the best one, which provided useful guidance for the design of new and efficient subtype selective JNK3 inhibitors.

Molecular Modeling Studies of Anti-Alzheimer Agents by QSAR, Molecular Docking and Molecular Dynamics Simulations Techniques.

Acetylcholinesterase (AChE), a serine hydrolase, is an important drug target in the treatment of Alzheimer's disease (AD). Thus, novel AChE inhibitors were designed and developed as potential drug candidates, for significant therapy of AD. In this work, molecular modeling studies, including CoMFA, CoMFA-RF, CoMSIA, HQSAR and molecular docking and molecular dynamics simulations were performed on a series of AChE inhibitors to get more potent anti-Alzheimer drugs. 2D/3D-QSAR models including CoMFA, CoMFA-RF, CoMSIA, and HQSAR methods were carried out on 40 pyrimidinylthiourea derivatives as data set by the Sybylx1.2 program. Molecular docking and molecular dynamics simulations were performed using the MOE software and the Sybyl program, respectively. Partial least squares (PLS) model as descriptors was used for QSAR model generation. The CoMFA (q2, 0.629; r2ncv, 0.901; r2pred, 0.773), CoMFA-RF (q2, 0.775; r2ncv, 0.910; r2pred, 0.824), CoMSIA (q2, 0.754; r2ncv, 0.919; r2pred, 0.874) and HQSAR models (q2, 0.823; r2ncv, 0.976; r2pred, 0.854) for training and test set yielded significant statistical results. These QSAR models were excellent, robust and had good predictive capability. Contour maps obtained from the QSAR models were validated by molecular dynamics simulationassisted molecular docking study. The resulted QSAR models could be useful for the rational design of novel potent AChE inhibitors in Alzheimer's treatment.

A Combined Molecular Docking and 3D‐QSAR Studies on Tetrahydropteridin Derivatives as PLK2 Antagonists

Polo‐like kinase‐2 (PLK2) is a member of a highly conserved serine/threonine kinase family. PLK2 is implicated in the regulation of cell division. It is activated in the early G1 phase in cell cycle progression and is required for centriole duplication. It has been observed that the low expression of PLK2 leads to B‐cell lymphoma and ovarian cancer. Furthermore, it was found to be associated with poor prognosis in non‐small cell lung cancer, breast cancer, head and neck carcinoma, and osteosarcoma. Thus, PLK2 is considered as an important therapeutic target for cancer drug design due to its multiple roles in several types of cancers. In this work, molecular docking and 3D‐QSAR techniques were performed on tetrahydropteridin derivatives as PLK2 inhibitors. Docking study identified crucial active site residues such as Leu88, Cys96, Ala109, Lys111, Val143, Leu159, Glu160, Cys162, and Phe212 which helps in the firm binding of the ligand. Receptor‐guided CoMFA (q 2 = 0.859, NOC = 5, r 2 = 0.996) and CoMSIA (q 2 = 0.855, NOC = 6, r 2 = 0.998) models were produced. The predictability and stability of these models were assessed using different validation techniques. Contour maps revealed that electrostatic and steric substitutions were favorable at R1 and R2 positions respectively. In addition, the substitution of H‐bond donor group at the R1 position was also favored. The results of this study could be helpful for designing more potent PLK2 inhibitors.

Synthesis, Antimicrobial Activity and 3D‐QSAR Study of Hybrid Oxazine Clubbed Pyridine Scaffolds

AbstractCompounds 1‐((1‐(4‐(2H‐benzo[e][1,3]oxazin‐3(4H)‐yl)phenyl)ethylidene)amino)‐6‐((arylidene)amino)‐4‐(4‐chlorophenyl)‐2‐oxo‐1,2‐dihydropyridine‐3,5‐dicarbonitriles (4a‐j) were prepared, characterized and screened for antimicrobial activity. 3D‐quantitative structure activity relationship (3D‐QSAR) was explained by CoMFA and CoMSIA models to rationalize the antimicrobial activity of the titled compounds. Statistically significant 3D‐QSAR (CoMFA and CoMSIA) models were created which could provide valuable information about the structural modification desired to improvise the biological activity. Additionally, the predictions based on the molecular docking study, against microbial DNA gyrase, were carried out.

Towards to potential 2-cyano-pyrimidines cathepsin-K inhibitors: An in silico design and screening research based on comprehensive application of quantitative structure–activity relationships, molecular docking and ADMET prediction

Cathepsin K (CK) is the only cathepsin showing high expression in osteoclasts. CK is considered to be a drug target in treatment of osteoporosis, rheumatoid arthritis and osteoarthritis. Comprehensive application of quantitative structure–activity relationships (QSAR), molecular docking and absorption, distribution, metabolism, excretion and toxicity (ADMET) prediction was conducted for designing and screening for potential CK inhibitors based on 2-cyano-pyrimidine analogs. For the two-dimensional (2D)-QSAR study, a statistical model of PLS_FCFP was chosen for its best evaluated regression statistic values (r2 = 0.759, q2 = 0.637 and r2pred = 0.699). An equation that implied positive or negative contributions for several molecular descriptors was acquired. For the 3D-QSAR study, based on two methods of generation of molecular poses, three fingerprint-based cluster partitions, and two common substructures, 336 candidate CoMFA and CoMSIA models were generated for evaluation of statistic values. Among them, database Minimize_MDL_subs01 provided superior evaluated models: CoMFA model #41 (r2 = 0.994, q2 = 0.746 and r2pred = 0.8693) and CoMSIA model #42 (r2 = 0.983, q2 = 0.753 and r2pred = 0.8676). Informative clues for molecular design were derived from the created QSAR models and, based on them, an in-house library containing 190 purposefully designed unknown compounds was built for screening for potential CK inhibitors. Based on a combination of activity prediction and calculation of binding affinity, unknown compound X139 emerged. Detailed molecular docking studies assisted in unveiling of the interactions between unknown compounds and the target protein. The strong π–π conjugation and preferably formed hydrogen bonds provided evidence that compound X139 had higher predicted activity. The subsequent study of ADMET prediction suggested acceptable drug-like properties for compound X139.

3D-QSAR, molecular docking, and new compound design of pyrimidine derivatives as Src small molecule inhibitors

Non-receptor tyromethod, The sine kinase Src is one of the important molecular targets for potential triple-negative breast cancer (TNBC). In this study, the structure and acitivity relationship of 51 Src small molecule inhibitors with potential pyrimidine derivatives was explored. On the basis of ligand composite, the relationsConducted a phase hip between molecular structure and inhibitory activity of MDA-MB-231/435 TNBC cell lines was studied by using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis fields (CoMSIA), and Topomer CoMFA (T-COMFA) methods, and thereby two sets of three-dimensional quantitative structure–activity relationship models were established to analyze the molecular structure and anti-TNBC activity. The results indicated that the q2 of CoMFA, CoMSIA, and Topomer CoMFA models was 0.698/0.719, 0.73/0.684, 0.674/0.683, and r2 was 0.994/0.991, 0.991/0.985, 0.946/0.959, respectively. Moreover, the three-dimensional equipotential map also revealed the relationship between structural characteristics and inhibitory activity, and molecular docking was investigated by Surflex-dock. The data proved that this model had good predictive ability and can further guide the design and modification of 3- (phenylethynyl) −1 hydropyrazolyl [3anilo-d] pyrimidine-4-amine derivatives inhibitors. According to the three-dimensional quantitative structure–activity relationship model of two TNBC cell lines of MDA-MB-231/435, 13 and 11 compounds were designed respectively, and the predicted activity values showed effective inhibition of SRC.

3D-QSAR modeling of Phosphodiesterase-5 inhibitors: evaluation and comparison of the receptor- and ligand-based alignments

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.