Pharmacophore‐based virtual screening (VS) has emerged as an efficient computer‐aided drug design technique when appraising multiple ligands with similar structures or targets with unknown crystal ...structures. Current pharmacophore modeling and analysis software suffers from inadequate integration of mainstream methods and insufficient user‐friendly program interface. In this study, we propose a stand‐alone, integrated, graphical software for pharmacophore‐based VS, termed ePharmer. Both ligand‐based and structure‐based pharmacophore generation methods were integrated into a compact architecture. Fine‐grained modules were carefully organized into the computing, integration, and visualization layers. Graphical design covered the global user interface and specific user operations including editing, evaluation, and task management. Metabolites prediction analysis with the chosen VS result is provided for preselection of wet experiments. Moreover, the underlying computing units largely adopted the preliminary work of our research team. The presented software is currently in client use and will be released for both professional and nonexpert users. Experimental results verified the favorable computing capability, user convenience, and case performance of the proposed software.
The pharmacophores are efficiently generated according to two different inputs, the ligand and the protein. The top n small molecules with the best matches (highest scores) are virtually screened through PharmFit algorithm from the small molecule database. The sorted small molecules and metabolites prediction are visualized for intuitive understanding and further analysis. Well‐designed user interface conveniently assists users to interactive operations including editing, evaluation and task management.
Objective: This study examined molecular docking and pharmacophore modeling to evaluate the potential antiparkinson activity of Kaempferol on various types and classes of receptors. Methods: The ...molecular docking was performed on various classes of receptors, namely transcription factor Nrf2, A2A Adenosine, and catechol-O-methyl transferase, using auto dock 4.0.1 software. Results: Kaempferol exhibited potential effects on two of the three tests (A2A adenosine and COMT receptors) as indicated by the lowest free energy binding values (-5.42 kcal/mol,-7.16 kcal/mol, and-8.33 kcal/mol, respectively). Kaempferol also had lower inhibitory constant values on transcription factor Nrf2, A2A adenosine, and COMT receptors (106.06 µM, 5.63 µM, and 779.51 nM, respectively). Kaempferol and the natural ligand had similar functional groups according to the critical components of the interaction between amino acid residues. The pharmacophore modeling revealed that hydroxyl functional groups strongly interact with crucial amino acid residues of the receptors. Conclusion: This study concludes that kaempferol is a potential antiparkinson agent against multiple receptors.
Hepatitis C is an infectious disease that leads to acute and chronic liver illnesses. Currently, there are no effective vaccines against this deadly virus. Direct acting antiviral (DAA) drugs are ...given in the combination with ribavirin and pegylated interferon which lead to adverse effects. Through in silico analysis, the structure‐based docking study was performed against NS3/4A protease and NS5B polymerase proteins of HCV. In the current study, multiple e‐pharmacophore‐based virtual screening methods such as HTVS, SP, and XP were carried out to screen natural compounds and enamine databases. Our result outcomes revealed that CID AE‐848/13196185 and CID AE‐848/36959205 compounds show good binding interactions with protease protein. In addition, CID 15081408 and CID 173568 show better binding interactions with the polymerase protein. Further to validate the docking results, we performed molecular dynamics simulation for the top hit compounds bound with protease and polymerase proteins to illustrate conformational differences in the stability compared with the active site of the cocrystal inhibitor. Thus, the current study emphasizes these compounds could be an effective drug to treat HCV.
With the discovery of P-glycoprotein (P-gp), it became evident that ABC-transporters play a vital role in bioavailability and toxicity of drugs. They prevent intracellular accumulation of toxic ...compounds, which renders them a major defense mechanism against xenotoxic compounds. Their expression in cells of all major barriers (intestine, blood–brain barrier, blood–placenta barrier) as well as in metabolic organs (liver, kidney) also explains their influence on the ADMET properties of drugs and drug candidates. Thus, in silico models for the prediction of the probability of a compound to interact with P-gp or analogous transporters are of high value in the early phase of the drug discovery process. Within this review, we highlight recent developments in the area, with a special focus on the molecular basis of drug–transporter interaction. In addition, with the recent availability of X-ray structures of several ABC-transporters, also structure-based design methods have been applied and will be addressed.
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DNA methyl transferases (DNMTs) are one of the crucial epigenetic modulators associated with a wide variety of cancer conditions. Among the DNMT isoforms, DNMT1 is correlated with bladder, ...pancreatic, and breast cancer, as well as acute myeloid leukemia and esophagus squamous cell carcinoma. Therefore, the inhibition of DNMT1 could be an attractive target for combating cancers and other metabolic disorders. The disadvantages of the existing nucleoside and non-nucleoside DNMT1 inhibitors are the main motive for the discovery of novel promising inhibitors. Here, pharmacophore modeling, 3D-QSAR, and e-pharmacophore modeling of DNMT1 inhibitors were performed for the large fragment database screening. The resulting fragments with high dock scores were combined into molecules. The current study revealed several constitutional pharmacophoric features that can be essential for selective DNMT1 inhibition. The fragment docking and virtual screening identified 10 final hit molecules that exhibited good binding affinities in terms of docking score, binding free energies, and acceptable ADME properties. Also, the modified lead molecules (GL1b and GL2b) designed in this study showed effective binding with DNMT1 confirmed by their docking scores, binding free energies, 3D-QSAR predicted activities and acceptable drug-like properties. The MD simulation studies also suggested that leads (GL1b and GL2b) formed stable complexes with DNMT1. Therefore, the findings of this study can provide effective information for the development/identification of novel DNMT1 inhibitors as effective anticancer agents.
•We used in silico studies in order to examine putative Farnesyltransferase inhibitors; a most recent and interesting area of selective ligand binding for Farnesyltransferase inhibition.•An attempt ...has been made for discovery of Farnesyltransferase specific inhibitors through 3D-QSAR pharmacophore modeling, virtual screening, molecular docking, molecular dynamics simulation, MM-PBSA and PCA techniques.•Our data may offer a platform for rational design of specific and potent inhibitor for Farnesyltransferase, with special emphasis on anti-cancer properties.
Farnesyltransferase (FTase) is considered as an effective target in treating a variety of cancers. In this investigation, a 3D-QSAR pharmacophore search was performed to identify potential inhibitors against FTase. Correspondingly, 3D-QSAR pharmacophore models for FTase inhibitors were generated utilizing the training set compounds and validated through the test set, cost analysis and Fischer's randomization test. The created pharmacophore models were evaluated based on Debnath's analysis. Then, the pharmacophore model Hypo1 was selected to perform pharmacophore-based screening. Subsequently, the identified compounds were filtered considering Lipinski's Rule of Five (RoF) and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties. In the next step, the inter-molecular interactions of the retrieved compounds and the most active compound of the training set with FTase were analyzed utilizing the flexible docking technique. Eventually, the best two compounds, ZINC08952683 and ZINC08918035, along with the reference compound, ZINC13559176, were selected for Molecular Dynamics (MD) studies in order to conduct an in-depth study on their complexes with FTase. MD results confirmed docking studies and showed that these two compounds could make stable complexes with the FTase active site and may have great inhibitory effects on FTase.
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In the present contribution, multicomplex‐based pharmacophore studies were carried out on the structural proteome of Plasmodium falciparum 1‐deoxy‐D‐xylulose‐5‐phosphate reductoisomerase. Among the ...constructed models, a representative model with complementary features, accountable for the inhibition was used as a primary filter for the screening of database molecules. Auxiliary evaluations of the screened molecules were performed via drug‐likeness and molecular docking studies. Subsequently, the stability of the docked inhibitors was envisioned by molecular dynamics simulations, principle component analysis, and molecular mechanics‐Poisson‐Boltzmann surface area‐based free binding energy calculations. The stability assessment of the hits was done by comparing with the reference (beta‐substituted fosmidomycin analog, LC5) to prioritize more potent candidates. All the complexes showed stable dynamic behavior while three of them displayed higher binding free energy compared with the reference. The work resulted in the identification of the compounds with diverse scaffolds, which could be used as initial leads for the design of novel PfDXR inhibitors.
This study was accomplished to bid healthier perceptive of multicomplex‐based pharmacophore screening in conjunction with molecular docking, molecular dynamics simulations, principle component analysis, and free energy calculations to search for Plasmodium falciparum 1‐deoxy‐d‐xylulose‐5‐phosphate reductoisomerase (
PfDXR) inhibitors.
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