Molecular dynamics-based insight of VEGFR-2 kinase domain: a combined study of pharmacophore modeling and molecular docking and dynamics.

BACKGROUND: Inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase by small molecules has become a promising target in the treatment of cancer. OBJECTIVE: In this study, we approached pharmacophore modeling coupled with a structure-based virtual screening workflow to identify the potent inhibitors. METHODS: The top selected hit compounds have been rescored using the MM/GBSA approach. To understand the molecular reactivity, electronic properties, and stability of those inhibitors, we have employed density functional theory and molecular dynamics. Following that, the best 21 hit compounds have been further post-processed with a Quantum ligand partial charge-based rescoring process and further validated by implementing molecular dynamics simulation. RESULTS: The ten hit compounds have been hypothesized and considered as potent inhibitors of VEGFR-2 tyrosine kinase. This study also signifies the contribution of QM-based ligand partial charge, which is more accurate in predicting reliable free binding energy and filtering large ligand libraries to hit optimization, rather than assigning those of the force field-based method. From the binding pattern analysis of all the complexes, amino acids, such as Glu885, Cys919, Cys1045, Thr916, Thr919, and Asp1046, were found to have comprehensive interaction with the hit compounds. CONCLUSION: Hence, this could prove to be useful as a potential inhibition site of the VEGFR-2 tyrosine kinase domain for future researchers. Moreover, this study also emphasizes the conformational changes upon ATP binding, based on either the receptor's rigidity or flexibility.

Exploring the potent inhibitors and binding modes of phospholipase A2 through in silico investigation.

Snake venom of Naja naja comprises of several types of enzymes, and among them, water-soluble proteolytic enzyme, phospholipase A2 (PLA2), is noteworthy for its numerous adverse effects, such as cytotoxicity, cardiotoxicity, hemolytic, anti-coagulant, and hypotensive effects, including being highly potent as a neurotoxin. Limited anti-venom therapy (with their lower efficacy) has attracted considerable pharmacological interest to develop potent inhibitors of PLA2. Thus, 34 experimentally proven and diverse synthetic inhibitors of PLA2 were screened primarily on the basis of Glide extra precision docking and MM-GBSA rescoring function. Then, ten potential hits were subjected to induced fit docking, in which top three potential inhibitors were considered, and those were found to interact with Ca2+, disulfide binding site, and phosphatidylcholine activation sites, thereby, possibly disrupting the catalytic activity of Ca2+ as well as the inflammatory functions of PLA2. These compounds showed positive remarks on various physiochemical properties and pharmacologically relevant descriptors. Gap energy and thermodynamic properties were investigated by employing density functional theory for all compounds to understand their chemical reactivity and thermodynamic stability. Molecular dynamics simulation was performed for 100 ns in order to evaluate the stability and binding modes of docked complexes, and the energy of binding was calculated through MM-PBSA analysis. On the whole, the proposed compounds could be used for targeted inhibition. Communicated by Ramaswamy H. Sarma.

Early implementation of guidelines for managing young infants with possible serious bacterial infection in Bangladesh.

Neonatal infections remain a leading cause of newborn deaths globally. In 2015, WHO issued guidelines for managing possible serious bacterial infection (PSBI) in young infants (0-59 days) with simpler antibiotic regimens if hospital referral is not feasible. Bangladesh was one of the first countries to adapt WHO guidance into national guidelines for implementation in primary healthcare facilities. Early implementation was led by the Ministry of Health and Family Welfare (MOHFW) in 10 subdistricts of Bangladesh with support from USAID's MaMoni Health System Strengthening project. This mixed methods implementation research case study explores programme feasibility and acceptability through analysis of service delivery data from 4590 sick young infants over a 15-month period, qualitative interviews with providers and MOHFW managers and documentation by project staff. Multistakeholder collaboration was key to ensuring facility readiness and feasibility of programme delivery. For the 514 (11%) infants classified as PSBI, provider adherence to prereferral treatment and follow-up varied across infection subcategories. Many clinical severe infection cases for whom referral was not feasible received the recommended two doses of injectable gentamicin and follow-up, suggesting delivery of simplified antibiotic treatment is feasible. However, prereferral antibiotic treatment was low for infants whose families accepted hospital referral, which highlights the need for additional focus on managing these cases in training and supervision. Systems for tracking sick infants that accept hospital referral are needed, and follow-up of all PSBI cases requires strengthening to ensure sick infants receive the recommended treatment, to monitor outcomes and assess the effectiveness of the programme. Only 11.2% (95% CI 10.3 to 12.1) of the expected PSBI cases sought care from the selected service delivery points in the programme period. However, increasing trends in utilisation suggest improved awareness and acceptability of services among families of young infants as the programme matured. Future programme activities should include interviews with caregivers to explore the complexities around referral feasibility and acceptability of simplified antibiotic treatment.

Quantum chemical calculation and binding modes of H1R; a combined study of molecular docking and DFT for suggesting therapeutically potent H1R antagonist.

Histamine-1 receptor (H1R) belongs to the family of rhodopsin-like G-protein-coupled receptors expressed in cells that mediates allergies and other pathophysiological diseases. For alleviation of allergic symptoms, H1R antagonists are therapeutic drugs; of which the most frequently prescribed are second generation drugs, such as; Cetirizine, Loratadine, Hydroxyzine, Desloratadine, Bepotastine, Acrivastine and Rupatadine. To understand their potency, binding affinity and interaction; we have employed molecular docking and quantum chemical study such as; Induced-fit docking and calculation of quantum chemical descriptors. This study also introduces the binding site characterization of H1R, with its known antagonists and Curcumin (our proposed alternative H1R antagonist); useful for future drug target site. The interactive binding site residues of H1R are found to be; Lys-191, Tyr-108, Asp-107, Tyr-100, Lys-179, Lys-191, Thr-194, Trp-428, Phe-432, Tyr-458, Hie-450, with most of these shown to be inhibited by naturally-occurring compound curcumin. Amongst the FDA approved drugs, Hydroxyzine showed best ligand binding affinity, calculated as - 141.491 kcal/mol and naturally occurring compound, Curcumin showed binding affinity of - 87.046 kcal/mol. The known antagonists of H1R has been used for hypothesizing curcumin as naturally occurring lead compound for the target using accurate molecular docking simulation study. Though the pharmacological action of known inhibitor is already established, they could differ from their reactivity, which we have also focused in our study for predicting drug reactivity.