Unveiling of Pyrimidindinones as Potential Anti-Norovirus Agents—A Pharmacoinformatic-Based Approach

The RNA-dependent RNA polymerase (RdRp) receptor is an attractive target for treating human norovirus (HNV). A computer-aided approach like e-pharmacophore, molecular docking, and single point energy calculations were performed on the compounds retrieved from the Development Therapeutics Program (DTP) AIDS Antiviral Screen Database to identify the antiviral agent that could target the HNV RdRp receptor. Induced-fit docking (IFD) results showed that compounds ZINC1617939, ZINC1642549, ZINC6425208, ZINC5887658 and ZINC32068149 bind with the residues in the active site-B of HNV RdRp receptor via hydrogen bonds, salt bridge, and electrostatic interactions. During the molecular dynamic simulations, compounds ZINC6425208, ZINC5887658 and ZINC32068149 displayed an unbalanced backbone conformation with HNV RdRp protein, while ZINC1617939 and ZINC1642549 maintained stability with the protein backbone when interacting with the residues. Hence, the two new concluding compounds discovered by the computational approach can be used as a chemotype to design promising antiviral agents aimed at HNV RdRp.

Evaluation of the IKKβ Binding of Indicaxanthin by Induced-Fit Docking, Binding Pose Metadynamics, and Molecular Dynamics

Background: Indicaxanthin, a betaxanthin belonging to the betalain class of compounds, has been recently demonstrated to exert significant antiproliferative effects inducing apoptosis of human melanoma cells through the inhibition of NF-κB as the predominant pathway. Specifically, Indicaxanthin inhibited IκBα degradation in A375 cells. In resting cells, NF-κB is arrested in the cytoplasm by binding to its inhibitor protein IκBα. Upon stimulation, IκBα is phosphorylated by the IKK complex, and degraded by the proteasome, liberating free NF-κB into the nucleus to initiate target gene transcription. Inhibition of the IKK complex leads to the arrest of the NF-κB pathway.Methods: To acquire details at the molecular level of Indicaxanthin’s inhibitory activity against hIKKβ, molecular modeling and simulation techniques including induced-fit docking (IFD), binding pose metadynamics (BPMD), molecular dynamics simulations, and MM-GBSA (molecular mechanics-generalized Born surface area continuum solvation) have been performed.Results: The computational calculations performed on the active and inactive form, and the allosteric binding site of hIKKβ, revealed that Indicaxanthin inhibits prevalently the active form of the hIKKβ. MM-GBSA computations provide further evidence of Indicaxanthin’s stability inside the active binding pocket with a binding free energy of −22.2 ± 4.3 kcal/mol with respect to the inactive binding pocket with a binding free energy of −20.7 ± 4.7 kcal/mol. BPMD and MD simulation revealed that Indicaxanthin is likely not an allosteric inhibitor of hIKKβ.Conclusion: As a whole, these in silico pieces of evidence show that Indicaxanthin can inhibit the active form of the hIKKβ adding novel mechanistic insights on its recently discovered ability to impair NF-κB signaling in melanoma A375 cells. Moreover, our results suggest the phytochemical as a new lead compound for novel, more potent IKKβ inhibitors to be employed in the treatment of cancer and inflammation-related conditions.

A multi-target approach for the discovery of Anti Breast Cancer Agents from Plants Secondary Metabolites

Background: Cancer is a multifactorial disease with multiple complications involving multiple proteins. Breast cancer is the most prevalent form of cancer among women. The pathophysiology of this cancer form has implicated several genetic alterations in its hallmark. Two of the most studied breast cancer molecular pathways are the cell cycle protein kinases and P13/AKT signalling pathway. Objective: Thus, this study identified novel inhibitors through computational screening of a library of medicinal plants compounds against cyclin-dependent kinase 2 (CDK2), phosphoinositide-3-kinase A (PI3Ka) and protein kinase B (AKT1). Methods: Rigid protein docking via Glide algorithm was applied to identify the hits from 3000 plants compounds screened against three drug targets involved in breast cancer pathogenesis. A more accurate and reliable ligand-protein docking called induced fit docking was adopted to extensively improve the scoring function by ranking favourable binding as top-scoring one. Results: Nine hit compounds were identified and found to interact with essential residues at the proteins’ binding sites. Subsequently, the hits pharmacokinetic parameters and toxicity were predicted to determine their potential as drug candidates and minimise toxic effects. The hit compounds were found to be non-carcinogenic, and five of them showed a desirable drug-like property. The built predictive QSAR models with an R2 value of 0.7684, 0.7973 and 0.5649 for CDK2, AKT1 and PI3Ka, respectively were adopted to determine the hits inhibitory activity (pIC50) against the screened proteins; and the predictions revealed compounds with significant activity. Three thousand (3000) compounds from diverse medicinal plants were docked with CDK2, AKT1 and PI3Ka to identify the top-scoring compounds using Glide algorithm scoring function. The identified compounds with low binding energies against the three targets were subsequently subjected to a more accurate and reliable ligand-protein docking called induced fit docking to extensively improve the compounds binding affinity with the proteins. Nine (9) compounds identified as hits were found to form highly stable complexes with the proteins and interacted with essential residues at the proteins’ binding sites. Prediction of the hit compounds drug-likeness, pharmacokinetic and toxicity properties by online web servers showed that the compounds are non-carcinogenic and showed moderate indices for ADMET parameters. The constructed QSAR models with reliable R2 coefficient value were used to predict the pIC50 of the selected compounds. The results revealed potent compounds with significant activity. Concluson: This study thus provides insight into multi-target protein compounds which could be explored as chemotherapeutic alternatives in breast cancer treatment.

Piperazine sulfonamides as DPP-IV inhibitors: Synthesis, induced-fit docking and in vitro biological evaluation

Diabetes mellitus is a chronic illness that needs persistent medical attention and continuous patient self-management to avoid acute complications. Dipeptidyl peptidase-IV (DPP-IV) inhibitors minimize glucagon and blood glucose levels by increasing the incretin levels, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic poly-peptide (GIP), leading to insulin secretion from pancreatic beta cells. In the present study, nine 1,4-bis(phenylsulfonyl) piperazine derivatives 1a-i were synthesized and identified using 1H NMR, 13C NMR, MS and IR spectroscopies. These compounds were tested in vitro and showed inhibitory activity ranging from 11.2 to 22.6 % at 100 µmol L–1 concentration. Piperazine sulfonamide derivatives were found to be promising DPP-IV inhibitors, where the presence of electron-withdrawing groups such as Cl (1a-c) improved the activity of the compounds more than electron-donating groups such as CH3 ( 1d-f) at the same position. Additionally, meta-substitution is disfavored (1b, 1e, 1g). Induced-fit docking studies suggested that the targeted compounds 1a-i occupy the binding domain of DPP-IV and form H-bonding with the backbones of R125, E205, E206, F357, K554, W629, Y631, Y662 and R669.

Induced Fit Docking and Automated QSAR Studies Reveal the ER-α Inhibitory Activity of Cannabis sativa in Breast Cancer

Background: Breast Cancer (BC), a common death-causing disease and the deadliest cancer next to lung cancer, is characterized by an abnormal growth of cells in the tissues of the breast. BC chemotherapy is marked by targeting the activities of some receptors such as Estrogen Receptor alpha (ER-α). At present, one of the most commonly used and approved marketed therapeutic drug for BC is tamoxifen. Despite the short term success of tamoxifen usage, its long time treatment has been associated with significant side effects. Therefore, there is a pressing need for the development of novel anti-estrogens for the prevention and treatment of BC. Objective: In this study, we evaluate the inhibitory effect of Cannabis Sativa phyto-constituents on ER-α. Method: Glide and Induced Fit Docking followed by ADME, Automated QSAR and Binding free energy (ΔGbind) studies were used to evaluate the anti-breast cancer and ER-α inhibitory activity of Cannabis sativa, which has been reported to be effective in inhibiting breast cancer cell proliferation. Results: Phyto-constituents of Cannabis sativa possess lower docking scores and good ΔGbind when compared to that of tamoxifen. ADME and AutoQSAR studies revealed that our lead compounds demonstrated the properties required to make them promising therapeutic agents. Conclusion: The results of this study suggest that Naringenin, Dihydroresveratrol, Baicalein, Apigenin and Cannabitriol could have relatively better inhibitory activity than tamoxifen and could be a better and patent therapeutic candidate in the treatment of BC. Further research such as in vivo and/or in vitro assays could be conducted to attest the ability of these compounds.

Molecular Interaction and Inhibitory Activity of Dandelion’s Compounds on Nucleoprotein: A Therapeutic Intervention in Lassa Fever

Lassa fever (LF) is an acute and sometimes fatal viral hemorrhagic fever caused by the Lassa virus (LASV). It is a major public health challenge and endemic exclusively in West Africa. Despite the large toll of human morbidity and mortality, no vaccine or effective drugs are available to treat this disease. Therefore, there is an urgent need for the development of novel and effective treatments and therapeutics. LASV nucleoprotein plays a vital role in several aspects of the viral life cycle. Therefore, an effective inhibitor of LASV nucleoprotein will potentially control the replication of LASV. To evaluate the inhibitory effect of Dandelion phyto-compounds on LASV nucleoprotein, Glide-SP, and –XP docking was performed for hit identification. The hit compounds were further subjected to Induced Fit Docking (IFD) followed by Prime MM-GBSA calculation and ADME studies. Dandelion phyto-compounds, carfentrazone, luteolin, caffeic acid, and riboflavin recorded better binding affinity than the reference drug, ribavirin, and interacted with key amino acids residues. ADME studies also showed that our hit compounds are drug-like. This study showed that phyto-compounds of dandelion could be a better and effective therapeutics in LF treatment.

N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamides: Molecular Docking, Synthesis, and Biological Investigation as Anticancer Agents

Cancer is a multifactorial disease and the second leading cause of death worldwide. Diverse factors induce carcinogenesis, such as diet, smoking, radiation, and genetic defects. The phosphatidylinositol 3-kinase (PI3Kα) has emerged as an attractive target for anticancer drug design. Eighteen derivatives of N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamide were synthesized and characterized using FT-IR, NMR (1H and 13C), and high-resolution mass spectra (HRMS). The series exhibited distinct antiproliferative activity (IC50 µM) against human epithelial colorectal adenocarcinoma (Caco-2) and colon carcinoma (HCT-116) cell lines, respectively: compounds 16 (37.4, 8.9 µM), 18 (50.9, 3.3 µM), 19 (17.0, 5.3 µM), and 21 (18.9, 4.9 µM). The induced-fit docking (IFD) studies against PI3Kαs showed that the derivatives occupy the PI3Kα binding site and engage with key binding residues.

A Reliable and Accurate Solution to the Induced Fit Docking Problem for Protein-Ligand Binding

We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore docking (Phase), rigid receptor docking (Glide), and protein structure prediction (Prime) with explicit solvent molecular dynamics simulations. We provide an in-depth description of our novel methodology and present results for 41 targets consisting of 415 cross-docking cases divided amongst a training and test set. For both the training and test-set, we compute binding modes with a ligand-heavy atom RMSD to within 2.5 Å or better in over 90% of cross-docking cases compared to less than 70% of cross-docking cases using our previously published induced-fit docking algorithm and less than 41% using rigid receptor docking. Applications of the predicted ligand-receptor structure in free energy perturbation calculations is demonstrated for both public data and in active drug discovery projects, both retrospectively and prospectively.