Computational studies reveal potential dolichyl-phosphate N-acetylglucosaminephosphotransferase inhibitors amidst existing drugs.

Dolichyl-phosphate N-acetylglucosaminephosphotransferase (dpagt1) inhibition is reported to kill tumor cells whose growth progression requires increased branching of N-linked glycans. Available dpagt1 inhibitors are grossly limited and are faced with problems of heamolytic effect and aqueous solubility thereby necessitating the search for new, safe and effective dpagt1 inhibitors. We employed computational methods to screen a dataset of ∼1300 FDA approved drugs in order to obtain theoretical dpagt1 inhibitors which could be repurposed as chemotherapeutic drugs. Top six better performing drugs, binding affinity for dpagt1 at the range of -17.63 to -20.40 kcal/mol, than the reference ligand (tunicamycin; -14.86 kcal/mol) were obtained at the end of structure-based-pharmacophore- and virtual-screening and 'induced fit' docking calculations. Analysis of their binding poses identified essential pharmacophores involved in target-ligand complexation that could be targeted in chemical modification to develop more effective and safe dpagt1 inhibitors.Communicated by Ramaswamy H. Sarma.

New sulphonamide-peptide hybrid molecules as potential PBP 2a ligands and methicillin resistant Staphylococcus aureus actives.

Penicillin binding protein 2a (PbP 2a) expression accounts for the insusceptibility of methicillin-resistant Staphylocuccus aureus (MRSA) to ß-lactam antibiotics. Here we employed computational strategies to challenge PbP 2a with series of fifty-five 'ala-ala' and 'ala-pro' sulphonamide-dipeptides. Binding stability of two compounds (labeled: 10i and 10n) with theoretical Ki in nM and µM ranges, for PbP 2a active and allosteric sites respectively, were investigated using molecular dynamics simulations. In addition, the results of the sensitivity of four strains of MRSA for compounds 10i and 10n obtained revealed the compounds at 10 µg/ml caused two isolates (S4 and S10) to revert to being susceptible. Finally, a reliable binding conformations of both compounds in the two binding sites of PbP 2a are described to provide rationale for structure-activity optimization of this series.Communicated by Ramaswamy H. Sarma.

In-silico molecular modelling, MM/GBSA binding free energy and molecular dynamics simulation study of novel pyrido fused imidazo[4,5-c]quinolines as potential anti-tumor agents.

With an alarming increase in the number of cancer patients and a variety of tumors, it is high time for intensive investigation on more efficient and potent anti-tumor agents. Though numerous agents have enriched the literature, still there exist challenges, with the availability of different targets and possible cross-reactivity. Herein we have chosen the phosphoinositide 3-kinase (PI3K) as the target of interest and investigated the potential of pyrido fused imidazo[4,5-c]quinoline derivatives to bind strongly to the active site, thereby inhibiting the progression of various types of tumors. The AutoDock, Glide and the Prime-MM/GBSA analysis are used to execute the molecular docking investigation and validation for the designed compounds. The anti-tumor property evaluations were carried out by using PASS algorithm. Based on the GLIDE score, the binding affinity of the designed molecules towards the target PI3K was evaluated. The energetics associated with static interactions revealed 1j as the most potential candidate and the dynamic investigations including RMSD, RMSF, Rg, SASA and hydrogen bonding also supported the same through relative stabilization induced through ligand interactions. Subsequently, the binding free energy of the Wortmannin and 1j complex calculated using MM-PBSA analysis. Further evaluations with PASS prediction algorithm also supported the above results. The studies reveal that there is evidence for considering appropriate pyrido fused imidazo[4,5-c]quinoline compounds as potential anti-tumor agents.

Inhibition of multiple SARS-CoV-2 proteins by an antiviral biomolecule, seselin from Aegle marmelos deciphered using molecular docking analysis.

Our earlier experimental and computational report produced evidence on the antiviral nature of the compound seselin purified from the leaf extracts of Aegle marmelos against Bombyx mori Nuclear Polyhedrosis Virus (BmNPV). In the pandemic situation of COVID-19 caused by the SARS-COV-2 virus, an in silico effort to evaluate the potentiality of the seselin was made to test its efficacy against multiple targets of SARS-COV-2 such as spike protein S2, COVID-19 main protease and free enzyme of the SARS-CoV-2 (2019-nCoV) main protease. The ligand seselin showed the best interaction with receptors, spike protein S2, COVID-19 main protease and free enzyme of the SARS-CoV-2 (2019-nCoV) main protease with a binding energy of -6.3 kcal/mol, -6.9 kcal/mol and -6.7 kcal/mol, respectively. Docking analysis with three different receptors identified that all the computationally predicted lowest energy complexes were stabilized by intermolecular hydrogen bonds and stacking interactions. The amino acid residues involved in interactions were ASP1184, GLU1182, ARG1185 and SER943 for spike protein, SER1003, ALA958 and THR961 for COVID-19 main protease, and for SARS-CoV-2 (2019-nCoV) main protease, it was THR111, GLN110 and THR292. The MD simulation and MM/PBSA analysis showed that the compound seselin could effectively bind with the target receptors. The outcome of pharmacokinetic analysis suggested that the compound had favourable drugability properties. The results suggested that the seselin had inhibitory potential over multiple SARS-COV-2 targets and hold a high potential to work effectively as a novel drug for COVID-19 if evaluated in experimental setups in the foreseeable future. Communicated by Ramaswamy H. Sarma.

Identification of Potential Therapeutics to Conquer Drug Resistance in Salmonella typhimurium: Drug Repurposing Strategy.

BACKGROUND: Salmonella typhimurium is the main cause of gastrointestinal illness in humans, and treatment options are decreasing because drug-resistant strains have emerged. OBJECTIVE: The objective of this study was to use computational drug repurposing to identify a novel candidate with an effective mechanism of action to circumvent the drug resistance. METHODS: We used the Mantra 2.0 database to initially screen drug candidates that share similar gene expression profiles to those of quinolones. Data were further reduced using pharmacophore mapping theory. Finally, we employed molecular-simulation studies to calculate the binding affinity of the screened candidates with DNA gyrase, alongside an analysis of side effects. RESULTS: A total of 16 drug candidates from the Mantra 2.0 database were screened. The pharmacophoric features of the screened candidates were examined and nalidixic acid features compared using the PharamGist program. A total of 11 compounds with the highest pharmacophore score were considered for binding energy calculation. Finally, we analysed the side effects of the eight drug candidates that showed significant binding affinity in the simulation study. CONCLUSION: Overall, flufenamic acid and sulconazole may be potential drug candidates that could be studied in vitro to assess their resistance profile against Salmonella enterica Typhimurium.

Virtual screening for oseltamivir-resistant a (H5N1) influenza neuraminidase from traditional Chinese medicine database: a combined molecular docking with molecular dynamics approach.

The neuraminidase (NA) of the influenza virus is the target of antiviral drug, oseltamivir. Recently, cases are reported that Influenza virus becoming resistant to oseltamivir, necessitating the development of new long-acting antiviral compounds. Most importantly, H274Y mutation in neuraminidase exhibits high levels of resistance to oseltamivir. In this report, a novel class of lead molecule with potential NA inhibitory activity was found from the traditional Chinese medicine database (TCMD) using virtual screening approach. Initially ADME properties of the lead compounds were analyzed with respect to the Lipinski rule of five. Subsequently, the data reduction was carried out by employing molecular docking study. Final validation was done by means of molecular dynamic simulations. The toxicity profiles for the screened compound were also analyzed. The result indicates that neoglucobrassicin (a compound derived from TCMD) become a promising lead compound and be effective in treating oseltamivir-resistant influenza virus strains.