Common Pharmacophore Research Articles

Coumarin-1,2,3-triazole Hybrid Molecules: An Emerging Scaffold for Combating Drug Resistance.

Undoubtedly, antibiotics have saved billions of lives, but lack of novel antibiotics, development of resistance mechanisms in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria hamper the successful treatment of the infections. Due to the widespread emergence of resistance, even the new families of anti-microbial agents have a short life expectancy. Drugs acting on a single target often lead to drug resistance and are associated with various side effects. For overcoming this problem, either multidrug therapy, or a single drug acting on multiple targets may be used. The latter is called 'hybrid molecules,' which are formed by clubbing two biologically active pharmacophores together, with or without an appropriate linker. In this rapidly evolving era, the development of natural product-based hybrid molecules may be a super-alternative to multidrug therapy, for combating drug resistance caused by various bacterial and fungal strains. Coumarins (benzopyran-2-one) are one of the earliest reported plant secondary metabolites having a clinically proven diverse range of pharmacological properties. On the other hand, 1,2,3-triazole is a common pharmacophore in many drugs responsible for polar interactions, improving the solubility and binding affinity to biomolecular targets. In this review, we discuss recent advances in Coumarin-1,2,3-triazole hybrids as potential anti-bacterial agents, aiming to provide a useful platform for the exploration of new leads with a broader spectrum, more effectiveness and less toxicity with multiple modes of action for the development of cost-effective and safer drugs in the future.

Pharmacophore Modelling of Vanillin Derivatives, Favipiravir, Chloroquine, Hydroxychloroquine, Monolaurin and Tetrodotoxin as MPro inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)

Ligand-based pharmacophore modelling approach using four established antiviral drugs, namely remdesivir, lopinavir, ritonavir and hydroxychloroquine were analysed for COVID-19 inhibitors as training sets. Twenty vanillin derivatives together with monolaurin were used as test sets to evaluate potential as SARS-CoV-2 inhibitors. Structure-based pharmacophore modelling approach was also performed using Protein Data Bank information: PDB-5RE6, 5REX and 5RFZ in order to analyse the binding site and ligand-protein complex interactions. The pharmacophore modelling mode of 5RE6 displayed two Hydrogen Bond Acceptors (HBA) and one Hydrophobic (HY) interaction. Besides, the pharmacophore model of 5REX showed two HBA and two HY interactions. Finally, the pharmacophore model of 5RFZ showed three HBA and one HY interaction. Based on ligand-based approach, 20 Schiff-based vanillin derivatives, namely vanillin associated with methyl-6- aminopyridine-3-carboxylate (1), sepiapterin (2), 6-aminopyridine-3-carboxylic acid (3), 6-aminopyridine-2-carboxylic acid (4), pemoline (5), α-phenylglycine (6), 2-amino-4-hydroxy-3-methylpentanoic acid (7), 4-hydroxyphenylglycine (8), β-homoserine (9), allylglycine (10), oxamic acid (11) benzophenone hydrazine (12), 2-aminoadipic acid (13), D-alanyl-D-alanine (14), p-bromophenylalanine (15), nicotinic hydrazide (16), 4-hydroxybenzhydrazide (17), benzohydrazide (18), isonicotinic hydrazide (19), and phenylhydrazine (20) showed strong MPro inhibition activity. This was due to their good alignment and common features to PDB-5RE6. Similarly, monolaurin and tetrodotoxin displayed some significant activity against SARS-CoV-2. From structure-based approach, vanillin derivatives (1) to (12) displayed some potent MPro inhibition against SARS-CoV-2. Favipiravir, chloroquine and hydroxychloroquine also showed some significant MPro inhibition. Favipiravir showed good alignment and common pharmacophore features to PDB- 5RFZ, whereas chloroquine and hydroxychloroquine showed good alignment and common pharmacophore features to PDB-5REX.

Ligand-based pharmacophore modeling, virtual screening and biological evaluation to identify novel TGR5 agonists.

Takeda G-protein-coupled receptor 5 (TGR5) is emerging as an important and promising target for the development of anti-diabetic drugs. To understand the structural characteristics of TGR5 agonists, the common feature pharmacophore models were generated and molecular docking was performed. The ligand-based virtual screening combined with pharmacophore mapping and molecular docking was performed to identify novel nonsteroidal TGR5 agonists. Finally, 20 compounds were screened for in vitro TGR5 agonistic activity assay, and results showed most compounds exhibiting TGR5 agonistic activity at 40 μM. Among these compounds, V12 and V14 displayed obvious TGR5 agonist activity, with the EC50 values of 19.5 μM and 7.7 μM, respectively. Compounds V12 and V14 could be considered potential TGR5 agonist candidates and also may be used as initial hits for developing novel TGR5 agonists.

In Silico Anticancer Evaluation, Molecular Docking and Pharmacophore Modeling of Flavonoids against Various Cancer Targets

Background: Designing and development of molecules for cancer treatment useful and with no side effects are a big challenge for the researchers in the field of drug discovery. The use of phytochemicals for chemoprevention is gaining more advantages, and intake of flavonoids has proved to reduce the occurrence of various cancers. Objectives: The present study was focused on selecting eight flavonoids and study them by in silico methods to analyse the interactions, affinity and pharmacophoric features that participate in the interactions between the flavonoid and the active sites of different cancer targets. Methods: The cancer targets were downloaded from the protein data bank, and flavonoids from PubChem and were docked by Glide XP molecular docking method to find the molecular interactions. The binding energy was calculated by Prime MM-GBSA application and ADMET analysis by Qikprop of Schrodinger. The anticancer potential of flavonoids screening was based on an online tool, Pass predictor. Phase module was used to find the common pharmacophore features that participate in essential interactions between the flavonoid and the active site. Results: In this study, myricetin has proved to be the best flavonoid for the treatment of breast and lung cancer with docking score of -11.50 kcal/mol and -10.56 kcal/mol respectively, whereas, quercetin has proved to be the best for prostate and colorectal cancer with docking score of -14.18 kcal/mol and -12.94 kcal/mol, respectively. The responsible forces for the interaction of these flavonoids are hydrogen bond, hydrophobic interactions, polar and pi-pi stackings. The PASS tool predicted the anticancer potential for the flavonoids, in particular, myricetin had responded highly active for most cancer cells. The hypothesis AADRR_1 has the highest survival score, which indicates the best alignment of the active ligands and represents the best pharmacophore model for anticancer activity. Conclusion: This work has screened eight flavonoids against various cancer targets and shown the binding interactions between them, stating that myricetin is the suitable lead candidate for breast and lung cancer; whereas, quercetin is the best lead for prostate and colorectal cancer. And these data are about the results obtained from PASS predictor. Moreover, the pharmacophore model has generated for the flavonoids, which correlate activities with the spatial arrangement of various chemical features. Therefore, this investigation strongly suggests that these flavonoids can be used as leads as anticancer agents.

Methylene blue analogues: In vitro antimicrobial minimum inhibitory concentrations and in silico pharmacophore modelling

It has been shown that methylene blue has antimicrobial properties although few studies have determined its minimum inhibitory concentration (MIC), which is the gold standard used to measure antimicrobial activity. The exact antimicrobial mode of action of methylene blue is still unclear and to our knowledge no pharmacophore model has yet been created to investigate methylene blue's mode of action. The aim of this study was to determine the MIC of methylene blue and a number of its analogous against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, Salmonella enterica and Candida albicans, and to use these data to develop and validate a common feature pharmacophore model. Three statistical metrics, i.e. the enrichment factor (EF), hit rate (HR) and the area under the curve of a receiver operator characteristic (ROC-AUC), were used to determine the pharmacophore model's ability to differentiate between active/decoy compounds. The validated pharmacophore model was used to map similar antibacterial compounds in an attempt to elucidate methylene blue's antimicrobial mode of action. Most test compounds only had activity against S. aureus, S. epidermidis and K. pneumoniae. Dimethyl methylene blue, new methylene blue and acriflavine proved to be the most active compounds against S. aureus [1 µg/ml (dimethyl methylene blue); 4 µg/ml (new methylene blue); 8 µg/ml (acriflavine)], S. epidermidis [1 µg/ml (dimethyl methylene blue); 4 µg/ml (new methylene blue); 2 µg/ml (acriflavine)] and K. pneumoniae [8 µg/ml (dimethyl methylene blue); 0.5 µg/ml (new methylene blue); 2 µg/ml (acriflavine)]. A common feature pharmacophore model was created (rank score: 26.664, max. fit value: 4), which was able to accurately identify active methylene blue analogous out of the test set (EF2%: 51, HR2%: 100%, ROC-AUC: 1.00 ± 0.00). Six phenothiazine derivatives with known antibacterial activity had high fit values when mapped with the validated pharmacophore model, i.e. >3.4. Dimethyl methylene blue, new methylene blue and acriflavine had potent antibacterial activity against S. aureus, S. epidermidis and K. pneumoniae. The MIC data will allow other researchers to compare the activity across different laboratories. The common feature pharmacophore model was able to identify methylene blue analogous with known in vitro antibacterial activity out of a database containing active/decoy compounds and highlighted the importance of two hydrophobic features, an aromatic feature and a hydrogen bond acceptor. The validated pharmacophore model also correctly mapped six phenothiazine derivatives with known antibacterial activity suggesting that they may share a common antibacterial mechanism of action.

Development of multitarget inhibitors for the treatment of pain: Design, synthesis, biological evaluation and molecular modeling studies

Multitarget-directed ligands are a promising class of drugs for discovering innovative new therapies for difficult to treat diseases. In this study, we designed dual inhibitors targeting the human fatty acid amide hydrolase (FAAH) enzyme and human soluble epoxide hydrolase (sEH) enzyme. Targeting both of these enzymes concurrently with single target inhibitors synergistically reduces inflammatory and neuropathic pain; thus, dual FAAH/sEH inhibitors are likely to be powerful analgesics. Here, we identified the piperidinyl-sulfonamide moiety as a common pharmacophore and optimized several inhibitors to have excellent inhibition profiles on both targeted enzymes simultaneously. In addition, several inhibitors show good predicted pharmacokinetic properties. These results suggest that this series of inhibitors has the potential to be further developed as new lead candidates and therapeutics in pain management.

Prediction of Premature Termination Codon Suppressing Compounds for Treatment of Duchenne Muscular Dystrophy Using Machine Learning

A significant percentage of Duchenne muscular dystrophy (DMD) cases are caused by premature termination codon (PTC) mutations in the dystrophin gene, leading to the production of a truncated, non-functional dystrophin polypeptide. PTC-suppressing compounds (PTCSC) have been developed in order to restore protein translation by allowing the incorporation of an amino acid in place of a stop codon. However, limitations exist in terms of efficacy and toxicity. To identify new compounds that have PTC-suppressing ability, we selected and clustered existing PTCSC, allowing for the construction of a common pharmacophore model. Machine learning (ML) and deep learning (DL) models were developed for prediction of new PTCSC based on known compounds. We conducted a search of the NCI compounds database using the pharmacophore-based model and a search of the DrugBank database using pharmacophore-based, ML and DL models. Sixteen drug compounds were selected as a consensus of pharmacophore-based, ML, and DL searches. Our results suggest notable correspondence of the pharmacophore-based, ML, and DL models in prediction of new PTC-suppressing compounds.

Identification of the natural compound inhibitors against Plasmodium falciparum plasmepsin-II via common feature based screening and molecular dynamics simulations

Malaria is counted amongst the deadly disease caused by Plasmodium falciparum. Recently, plasmepsin-II enzyme has gained much importance as an attractive drug target for the exploration of antimalarials. Therefore, the common feature pharmacophore models were generated from the crystallized complexes of the plasmepsin-II proteome. These models were subjected to a series of validation procedures, i.e. test set and Güner Henry studies to enlist the representative models. The selected representative hypotheses incorporating the most essential chemical features (common ZHHA) were screened against the natural product database to retrieve the potential candidates. To ensure the selection of the drug-like candidates, prior to screening, filtering steps (Drug-likeness and ADMET filters) were employed on the selected database. To study the interaction pattern of the candidates within the protein, these molecules were advanced to the molecular docking studies. Subsequently, based on the selected cut-off criteria obtained via redocking of the reference (4Z22), 15 compounds showed higher docking score (> −16.05 kcal/mol), and displayed the presence of hydrogen bonding with the crucial amino acids, i.e. Asp34 and Asp214. Further, the stability of the docked molecules was scrutinized via molecular dynamics simulations, and the results were compared with the reference compound 4Z22. All the docked compounds showed stable dynamics behaviour. Thus, in the present contribution, the combination of screening and stability procedures resulted in the identification of 15 hits that can serve as a new chemical space in the designing of the novel antimalarials. Communicated by Ramaswamy H. Sarma

Molecular dynamics simulation for screening phytochemicals as α-amylase inhibitors from medicinal plants

Diabetes mellitus (DM) is a complicated metabolic disorder with several enzymes, including α-amylase and α-glycosidase. The α-amylase is responsible for postprandial glucose levels; therefore, inhibiting its activity is helpful in diabetes management. Hence, to find natural inhibitors of α-amylase, we have prepared a 257 phytochemical library from selected medicinal plants with antidiabetic activity and conducted a virtual screening and molecular dynamics study. Seventy-nine phytochemicals were screened out of 257 phytochemicals based on binding energy, ranged from −10.1 kcal mol−1 to −7.6 kcal mol−1. The binding energies of screened compounds were lower or equal to the reference molecule (−7.6 kcal mol−1). The binding affinity of six screened phytochemicals was re-scored by X-SCORE. These phytochemicals were subjected to ADMET and Drug-likeness analysis. After screening docking and drug-likeness analysis, six phytochemicals viz., Shahidine, Epicatechin, Quercetin, Isocolumbin, Ellagic acid, Luteolin and a reference molecule (Acarbose) were subjected to Molecular dynamics (MD) simulation to analyze the stability of the docked protein-ligand complex. The values of root mean square deviation, RMSF, RG, SASA, H-Bond, the interaction energy of all protein-ligand complexes were calculated after 30 ns of MD simulation. The results of screened complexes revealed good stability as compared to reference Acarbose. Pharmacophore features of the screened phytochemicals and α-amylase inhibitors showed many common pharmacophore features. Based on finding the screened phytochemicals, e.g. Shahidine, Epicatechin, Quercetin, Isocolumbin, Ellagic acid, and Luteolin, may be used as a potential inhibitors against α-amylase. These phytochemicals could be optimized and synthesized to develop potential drugs to manage and treat diabetes, targeting α-amylase. Communicated by Ramaswamy H. Sarma.

Pharmacophore Generation, Quantitative Structure-Activity Relationship (QSAR), and Molecular Dynamic Simulation of Newly Substituted N-(6- Chloro-3-cyano-4-phenyl-4H-chromen-2-yl)-2-(4-chloro-phenoxy)-acetamide for Anticancer Activity

The main objective of the study was to develop the Quantitative Structure- Activity Relationship (QSAR) and pharmacophore model by using data obtained from HT-29 cells to develop potent lead molecule for the scientific community. Common pharmacophore model, atom-based 3D-QSAR, and molecular dynamic (MD) simulation were carried out via computational techniques by using 4H-chromene derivatives. The reliable common pharmacophoric hypothesis, DHH13 was generated and 3.95 survival value was also found. Furthermore, the statistically significant 3D-QSAR model was developed where r2=0.52 was found by using the Partial least squares (PLS) regression method. Phase predicted activity and Log GI50 demonstrated an important atomic position in the structure of ligands to ascertain anti colon cancer activity. Also, MD simulation was carried out between top rank leads targeting IL-6 that provided better binding conformational and complex stability into the active pocket site of the target throughout the MD simulation. The outcome of this design shows that the pharmacophore model and 3D-QSAR might be helpful for researchers in the field of medicinal chemistry to design and develop potential anti colon cancer compounds.

Selective C-H trifluoromethoxylation of (hetero)arenes as limiting reagent

Methods for direct C-H trifluoromethoxylation of arenes and heteroarenes are rare, despite the importance of trifluoromethoxylated compounds for pharmaceuticals, agrochemicals, and material sciences. Especially selective C-H trifluoromethoxylation of pyridines remains a formidable challenge. Here we show a general late-stage C-H trifluoromethoxylation of arenes and heteroarenes as limiting reagent with trifluoromethoxide anion. The reaction is mediated by silver salts under mild reaction conditions, exhibiting broad substrate scope and wide functional-group compatibility. In addition, ortho-position selective C-H trifluoromethoxylation of pyridines is observed. The method is not only applicable to the gram-scale synthesis of trifluoromethoxylated products but also allows efficient late-stage C-H trifluoromethoxylation of marketed small-molecule drugs, common pharmacophores and natural products.

Reliable screening and classification of phosphodiesterase type 5 inhibitors in dietary supplements using gas chromatography / mass spectrometry combined with specific common ions

Illegal dietary supplements adulterated with phosphodiesterase type 5 inhibitors (PDE-5i) are increasingly widely distributed through internet markets and underground routes. For this reason, it demands development of reliable screening methods to determine a wide range of PDE-5i drugs in various types of dietary supplements. Herein, we developed a screening method using gas chromatography-mass spectrometry (GC–MS) for simultaneous detection of 53 PDE-5i drugs in supplements. Common formulations (such as capsule, powder, pill, and tablet) of supplements with complicated matrices were treated by simple liquid–liquid extraction and trimethylsilyl (TMS) derivatization. With the aid of TMS derivatization, 53 PDE-5i drugs could be successfully separated and detected within 15 min, using a short microbore GC column (15 m). Moreover, owing to enhanced detection sensitivity and selectivity of PDE-5i TMS derivatives, 0.5 mg of sample was sufficient to screen and confirm targeted PDE-5i drugs. In this study, specific common ions according to structural characteristics of PDE-5i drugs were found under the electron ionization (EI) of their TMS derivatives. These specific common fragments could reflect the common pharmacophores for 4 classes of PDE-5i drugs (sildenafil, other sildenafil, vardenafil, and tadalafil analogues). Based on characteristic EI fragment ions, extracted common ion chromatograms (ECICs) and discriminant analysis (DA) were effectively used for reliable screening and classification of various types of PDE-5i drugs. Specific ECICs and DA using characteristic EI fragments here will aid in identification of newly emerging PDE-5i counterfeits in supplements. This study will be helpful to supervise illegal adulteration of PDE-5i drugs in dietary supplements to protect public health and consumer safety.

Design and synthesis of imidazole based zinc binding groups as novel small molecule inhibitors targeting Histone deacetylase enzymes in lung cancer

Histone deacetylase enzymes are involved in the remodelling of chromatin and have a pivotal role in balancing acetylation and deacetylation status of chromatin eventually ensures the epigenetic regulation of gene expression. Its aberrant activity was reported in several forms of cancer considering it as a potential target for cancer treatment. Histone deacetylase inhibitors emerged as new class of antineoplastic drugs. Recent developments in understanding the mechanism of interaction between drug and targeted molecule encourages rational development of new class of HDAC inhibitors directing global or gene specific histone acetylation. In the present study, we designed 14 imidazole based derivatives abiding the common pharmacophore structure like CAP, Spacer, and Zinc binding group (ZBG) shared among the established HDAC inhibitors and was explored for its epigenetic modulator candidature targeting histone modifying enzymes through docking experiments. Among them the compound ethyl (2,5-diphenyl-1H-imidazole-4-yl)acetate (C3) was tightly bound to the isoforms of the HDAC enzymes at their receptor regions with high binding score. C3 was synthesized and have been characterized experimentally by IR and NMR techniques. The C3 inhibit cell proliferation of A549 lung cancer cell by inducing cytotoxicity and increased levels of ROS generation by disrupting mitochondrial permeability as evidenced from deflection in (Δψm). From this study we revealed that C3 a novel imidazole derivative inhibit highly expressed HDAC enzyme in non-small cell lung cancer cell lines by chromatin remodelling. Further findings may validate the identified compound C3 as an effective epigenetic modulator.

Dual potent c-Met and ALK inhibitors: from common feature pharmacophore modeling to structure based virtual screening

Everyday plenty of people succumb to various forms of cancer across the world and it stands as one of the main reasons of death in our today’s life. Receptor tyrosine kinases (RTKs) are a class of receptors involved in cancer progression. Since aberrant signaling has critical roles in cancer, both c-Met and ALK enzymes are regarded as attractive oncology targets for therapeutic objects. A number of potent dual inhibitors of c-Met and ALK are reported in literature that in the present work we based them to construct multiple common feature pharmacophore models and then applied them for ligand-based virtual screening. The score values of the models ranged from 22.489 to 28.169. The retrieved compounds from virtual screening were subjected to the docking study and the interaction pattern of common hits between two enzymes with high predicted affinity has been investigated. To this end, common hit compound ZINC000223394281 (z1) was directed to the molecular dynamics study and the results indicated that the hydrogen bond interaction between this compound and Asp1222 was mostly stable during the equilibrium time range. The life time of hydrogen bond made between the complex of ALK and Met1199 was also stable in 63%.

Design, synthesis, biological evaluation, common feature pharmacophore model and molecular dynamics simulation studies of ethyl 4-(phenoxymethyl)-2-phenylthiazole-5-carboxylate as Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors

SHP2 is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell death pathway (PD-1/PD-L1) and cell growth and differentiation pathway (MAPK). Moreover, mutations in SHP2 have been implicated in Leopard syndrome (LS), Noonan syndrome (NS), juvenile myelomonocytic leukemia (JMML) and several types of cancer and solid tumors. Thus, SHP2 inhibitors are much needed reagents for evaluation of SHP2 as a therapeutic target. A series of novel ethyl 4-(phenoxymethyl)-2-phenylthiazole-5-carboxylate derivatives were designed and synthesized, and their SHP2 inhibitory activities (IC50) were determined. Among the desired compounds, 1d shares the highest inhibitory activity (IC50 = 0.99 μM) against SHP2. Additionally, a common feature pharmacophore model was established to explain the structure activity relationship of the desired compounds. Finally, molecular dynamics simulation was carried out to explore the most likely binding mode of compound 1d with SHP2. In brief, the findings reported here may at least provide a new strategy or useful insights in discovering novel effective SHP2 inhibitors. Communicated by Ramaswamy H. Sarma

Palladium Catalyzed C−O Coupling of Amino Alcohols for the Synthesis of Aryl Ethers

AbstractAmine containing aryl ethers are common pharmacophore motifs that continue to emerge from drug discovery efforts. As amino alcohols are readily available building blocks, practical methodologies for incorporating them into more complex structures are highly desirable. We report our efforts to explore the application of Pd‐catalyzed C−O coupling methods to the arylation of 1,2‐ and 1,3‐amino alcohols. We established general and reliable conditions, under which we explored the scope and limitations of the transformation. The insights gained have been valuable in employing this methodology within a fast‐moving drug discovery environment, which we anticipate will be of general interest to the synthesis and catalysis communities.magnified image

Isatin-azole hybrids and their anticancer activities.

Isatin and azole moieties, which have the ability to form various noncovalent interactions with different therapeutic targets, are common pharmacophores in drug development. Isatin and azole derivatives possess promising in vitro and in vivo anticancer activity, and many of them, such as semaxanib, sunitinib, and carboxyamidotriazole, could be used to treat various cancers. Thus, it is conceivable that hybridization of the isatin moiety with azole may provide a valuable therapeutic intervention for the treatment of cancer. Substantial efforts have been made to develop isatin-azole hybrids as novel anticancer agents, and some of the isatin-azole hybrids exhibited considerable activity. This review emphasizes isatin-azole hybrids with potential anticancer activity, covering articles published between 2010 and 2019. The structure-activity relationships as well as the mechanisms of action are also discussed to provide insights for the rational design of more effective candidates.

In silico screening of anti-inflammatory compounds from Lichen by targeting cyclooxygenase-2

Non-steroidal anti-inflammatory drugs (NSAID) targeting cyclooxygenase-2 are clinically effective. However, they lack anti-thrombotic activity resulting in incidences of adverse effects like myocardial infarction, gastrointestinal and abdominal discomfort which necessitate for discovering new drug candidates with improved therapeutic effects and tolerability. Various recent researches have suggested that many lichens offer a vast reservoir for anti-inflammatory drug candidates which are natural as well as safe for human consumption. Drug discovery is a very complex and time-consuming process; however, in silico techniques can make this process simple and economic. Hence to find out natural anti-inflammatory compounds, we have carried out the virtual screening of 412 lichen compounds by molecular docking with human Cox-2 enzyme and validated the docking score by X-Score followed by ADMET and Drug-likeness analysis. The resulting 6 top-scored compounds were subjected to Molecular dynamics simulation (MDS) to analyze the stability of docked protein-ligand complex, to assess the fluctuation and conformational changes during protein-ligand interaction. The values of RMSD, Rg, and interaction energy after 30 ns of MDS revealed the good stability of these Lichen compounds in the active site pocket of Cox-2 in compare to reference, JMS. Additionally, we have done the pharmacophore analysis which found many common pharmacophore features between Lichen compounds and well known anti-inflammatory compounds. Our result shows that these lichen compounds are potential anti-inflammatory candidates and could be further modified and evaluated to develop more effective anti-inflammatory drugs with fewer side effects for the treatment of inflammatory diseases.Communicated by Ramaswamy H. Sarma

Evaluation of the combination mode and features of p38 MAPK inhibitors: construction of different pharmacophore models and molecular docking

ABSTRACTAbnormal expression of tumour necrosis factor-α (TNF-α) can lead to various pathological reactions, such as arthritis, psoriasis, krone disease, etc. p38 mitogen-activated protein kinase (p38 MAPK) is an important signal transduction enzyme that plays important roles in influencing the release of intracellular TNF-α factor. It is very meaningful to study the targeting kinase with specific inhibitors in the treatment of related diseases. In order to achieve a deeper insight, it is necessary to analyse the structural characteristics and the action mode of the p38 MAPK inhibitors in the active site. In the study, a ligand-based common feature pharmacophore model and the receptor structure-based pharmacophore model were constructed, respectively. Their common chemical features consisted of the hydrophobic groups (H) and the hydrogen bond acceptors (A), and kept the consistency of spatial structure distribution. Then, the molecular docking and molecular dynamics simulation were performed with the eight training set compounds. The binding characteristics of molecules binding were described in the topological region of the active site. Finally, the structure–activity relationship (SAR) was obtained by analysing docking results with the different pharmacophore models. This research leads to the proposal of an interaction model in the p38 MAPK active site and provides guidance for the screening and design of more potent and selective p38 MAPK inhibitors.

Molecular modelling studies for 4-oxo-1,4-dihydroquinoline-3-carboxamide derivatives as anticancer agents

The ligand library reporting anticancer activities was taken from literature containing forty-two 4-oxo-1,4-dihydroquinoline-3-carboxamides derivatives and was thoroughly investigated against cancer target (pdb id-5U6B) using docking protocol. In order to design future analogues, we carried out our research to develop the Atom based- and Field based-3D QSAR (Quantitative structure–activity relationship models) models.PHASE was employed for the common pharmacophore generation and 3D-QSAR studies. The protein target (pdb id-5U6B) was selected and docking was used in order to check better binding modes between target and ligands. The crystal structure of Axl kinase domain in complex with a macrocyclic inhibitor complex (pdb id-5U6B) had a resolution of 2.84 Å. The free energy was calculated by using PRIME-Molecular mechanics with generalized Born and surface area solvation (MM/GBSA). The molecular properties and ADME parameter were calculated using Qikprop utility.Out of 12 developed pharmacophore hypothesis using the PHASE module, a six point AAHRRR_1 hypothesis found best with good scoring parameters involving the two acceptor features, one hydrophobic feature and three ring features. For the atom based-3D QSAR model, a good cross-validation correlation coefficient i.e. Q2 value as 0.5715 for test set and R2 (a correlation coefficient) as 0.8704 for training set molecules. In case of field based QSAR, a cross-validation correlation coefficient (Q2) for test set as 0.5697 and R2 (a correlation coefficient) as 0.817 for training set molecules. Both the models show good statistical significance for future designing. The compound 9L observed as best docked for target 5U6B having docking score of −4.085 kcal/mol and PRIME MM/GBSA (Prime/Molecular Mechanics Generalized Born Surface Area) dg bind energy as-63.302 kcal/mol. The values for rule of five for all dataset compounds were found within range. Percentage human oral absorption values were also >80% except few compounds. Finally, our current study will helpful for researchers in order to develop new 4-oxo-1,4-dihydroquinoline-3-carboxamides derivatives as more potent anticancer agents.