G-CSF primary prophylaxis use and outcomes in patients receiving chemotherapy at intermediate risk for febrile neutropenia: a scoping review.

INTRODUCTION: Febrile neutropenia (FN) is a major dose-limiting toxicity of myelosuppressive chemotherapy, and several patients receiving chemotherapy are at intermediate risk of developing FN. However, the guidelines remain less clear regarding the use of granulocyte colony-stimulating factors (G-CSFs) for this population and insights about real-world prophylaxis patterns and FN outcomes are needed. AREAS COVERED: This scoping review summarizes the variability in real-world G-CSF prophylaxis treatment patterns, incidence of FN, and associated outcomes among patients receiving chemotherapy at intermediate risk of FN. G-CSF PP use varied across the included studies (N = 23). Overall, there was a trend for reduced FN incidence among patients who received G-CSF PP vs. those who did not. G-CSF PP was also associated with a lower incidence of FN-related dose delays and reductions and fewer hospitalization days. Gaps in the literature of real-world studies exist, particularly around incorporating FN risk factor assessment, patient-reported outcomes, and health economic outcomes. EXPERT OPINION: Further studies are warranted to determine the impact of G-CSF PP use on clinical, quality of life, and economic outcomes in patients with intermediate FN risk, which could optimize care for this subgroup of patients, resulting in better population-based FN-related outcomes.

Chalcone Based Homodimeric PET Agent, 11C-(Chal)2DEA-Me, for Beta Amyloid Imaging: Synthesis and Bioevaluation.

Homodimeric chalcone based 11C-PET radiotracer, 11C-(Chal)2DEA-Me, was synthesized, and binding affinity toward beta amyloid (Aß) was evaluated. The computational studies revealed multiple binding of the tracer at the recognition sites of Aß fibrils. The bivalent ligand 11C-(Chal)2DEA-Me displayed higher binding affinity compared to the corresponding monomer, 11C-Chal-Me, and classical Aß agents. The radiolabeling yield with carbon-11 was 40-55% (decay corrected) with specific activity of 65-90 GBq/µmol. A significant ( p < 0.0001) improvement in the binding affinity of 11C-(Chal)2DEA-Me with synthetic Aß42 aggregates over the monomer, 11C-Chal-Me, demonstrates the utility of the bivalent approach. The PET imaging and biodistribution data displayed suitable brain pharmacokinetics of both ligands with higher brain uptake in the case of the bivalent ligand. Metabolite analysis of healthy ddY mouse brain homogenates exhibited high stability of the radiotracers in the brain with >93% intact tracer at 30 min post injection. Both chalcone derivatives were fluorescent in nature and demonstrated significant changes in the emission properties after binding with Aß42. The preliminary analysis indicates high potential of 11C-(Chal)2DEA-Me as in vivo Aß42 imaging tracer and highlights the significance of the bivalent approach to achieve a higher biological response for detection of early stages of amyloidosis.

Modified benzoxazolone derivative as 18-kDa TSPO ligand.

We have synthesized six new congeners of acetamidobenzoxazolone for Translocator Protein [18 kDa, TSPO] imaging. The best in vitro binding affinity (10.8 ± 1.2 nm) for TSPO was found for N-methyl-2-(5-(naphthalen-1-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)-N-phenylacetamide, (NBMP). NBMP was synthesised by Suzuki coupling reaction between 2-(5-bromo-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-phenylacetamide and napthalene-1-boronic acid. Computational docking and simulation studies showed not much impact of intersubject variability on binding which is one of the major drawbacks of several TSPO ligands. These findings suggested that NBMP may become a promising marker for visualization of neuroinflammation via TSPO targeting.

In Silico Designing and Analysis of Inhibitors against Target Protein Identified through Host-Pathogen Protein Interactions in Malaria.

Malaria, a life-threatening blood disease, has been a major concern in the field of healthcare. One of the severe forms of malaria is caused by the parasite Plasmodium falciparum which is initiated through protein interactions of pathogen with the host proteins. It is essential to analyse the protein-protein interactions among the host and pathogen for better understanding of the process and characterizing specific molecular mechanisms involved in pathogen persistence and survival. In this study, a complete protein-protein interaction network of human host and Plasmodium falciparum has been generated by integration of the experimental data and computationally predicting interactions using the interolog method. The interacting proteins were filtered according to their biological significance and functional roles. α-tubulin was identified as a potential protein target and inhibitors were designed against it by modification of amiprophos methyl. Docking and binding affinity analysis showed two modified inhibitors exhibiting better docking scores of -10.5 kcal/mol and -10.43 kcal/mol and an improved binding affinity of -83.80 kJ/mol and -98.16 kJ/mol with the target. These inhibitors can further be tested and validated in vivo for their properties as an antimalarial drug.

Preclinical Evaluation of a Potential GSH Ester Based PET/SPECT Imaging Probe DT(GSHMe)2 to Detect Gamma Glutamyl Transferase Over Expressing Tumors.

Gamma Glutamyl Transferase (GGT) is an important biomarker in malignant cancers. The redox processes ensuing from GGT-mediated metabolism of extracellular GSH are implicated in critical aspects of tumor cell biology. Reportedly, Glutathione monoethyl ester (GSHMe) is a substrate of GGT, which has been used for its rapid transport over glutathione. Exploring GGT to be an important target, a homobivalent peptide system, DT(GSHMe)2 was designed to target GGT-over expressing tumors for diagnostic purposes. DT(GSHMe)2 was synthesized, characterized and preclinically evaluated in vitro using toxicity, cell binding assays and time dependent experiments. Stable and defined radiochemistry with 99mTc and 68Ga was optimized for high radiochemical yield. In vivo biodistribution studies were conducted for different time points along with scintigraphic studies of radiolabeled DT(GSHMe)2 on xenografted tumor models. For further validation, in silico docking studies were performed on GGT (hGGT1, P19440). Preclinical in vitro evaluations on cell lines suggested minimal toxicity of DT(GSHMe)2 at 100 µM concentration. Kinetic analysis revealed transport of 99mTc-DT(GSHMe)2 occurs via a saturable high-affinity carrier with Michaelis constant (Km) of 2.25 µM and maximal transport rate velocity (Vmax) of 0.478 µM/min. Quantitative estimation of GGT expression from western blot experiments showed substantial expression with 41.6 ± 7.07 % IDV for tumor. Small animal micro PET (Positron Emission Tomography)/CT(Computed Tomography) coregistered images depicted significantly high uptake of DT(GSHMe)2 at the BMG-1 tumor site. ROI analysis showed high tumor to contra lateral muscle ratio of 9.33 in PET imaging studies. Avid accumulation of radiotracer was observed at tumor versus inflammation site at 2 h post i.v. injection in an Ehrlich Ascites tumor (EAT) mice model, showing evident specificity for tumor. We propose DT(GSHMe)2 to be an excellent candidate for prognostication and tumor imaging using PET/SPECT.

In silico thermodynamics stability change analysis involved in BH4 responsive mutations in phenylalanine hydroxylase: QM/MM and MD simulations analysis.

The mammalian tetrahydrobiopterin (BH4)-dependent phenylalanine hydroxylases (PAH), involved in important metabolic pathways of phenylalanine, belong to non-heme iron-containing aromatic acid hydroxylases' enzyme (AAH) family. AAHs utilize BH4 as protein co-factor and thus promote hydroxylation reactions of their substrates. Any alterations in BH4 -mediated AAH's pathway or mutations in these enzymes are responsible for various disorders, and thus highlights the importance of mutational analysis to assess the effect on their biosynthetic pathways. Our present studies are aimed at single-site mutations in PAH that lead to thermodynamic stability change upon folding and further validation of designed non-reduced BH2 designed co-factors. We have presented single-site mutational analysis of PAH where single-site mutations have been identified from known literature. Further, in silico studies with the PAH, in silico mutant PAH, and crystallized known mutant A313T forms, involved QM/MM and Molecular Dynamics (MD) simulations analysis. The modified co-factor A showed high affinity with PAH and all mutant PAH with high G-score of -14.851. The best pose high affinity co-factor A subjected to QM/MM optimization which leads to square-pyramidal coordination of non-heme active site. The structural and energetic information obtained from the production phase of 20 ns MD simulation of co-factor-metalloprotein complex results helped to understand the binding mode and involvement of three molecules throughout the reaction pathways' catalysis of PAH. The free energies of binding (dG) of A were found to be -68.181 kcal/mol and -72.249 for 1DMW and 1TDW for A313T mutant. Binding of Co-factor A do not perturb the coordination environment of iron at the active site which resides in 2-Histdine and 1-Glutamate triad, and may enhance the percentage response towards co-factor-mediated therapy.

Oxime-dipeptides as anticholinesterase, reactivator of phosphonylated-serine of AChE catalytic triad: probing the mechanistic insight by MM-GBSA, dynamics simulations and DFT analysis.

Neuropathological cascades leading to reduced cholinergic transmission in Alzheimer's disease led to development of AChE-inhibitors. Although lethal dose of some inhibitors cause interruption with AChE mediated mechanism but reversible AChE inhibitors can assist in protection from inhibition of AChE and hence in an aim to probe potential molecules as anticholinesterase and as reactivators, computationally structure-based approach has been exploited in this work for designing new 2-amino-3-pyridoixime-dipeptides conjugates. We have combined MD simulations with flexible ligand docking approach to determine binding specificity of 2-amino-3-pyridoixime dipeptides towards AChE (PDB 2WHP). PAS residues are found to be responsible for oxime-dipeptides binding along with π-π interactions with Trp86 and Tyr286, hydrogen bonding with side chains of Asp74 and Tyr341 (Gscore -10.801 and MM-GBSA free energy -34.89 kcal/mol). The docking results depicted complementary multivalent interactions along with good binding affinity as predicted from MM-GBSA analysis. The 2-amino-3-pyridoxime-(Arg-Asn) AChE systems subjected to MD simulations under explicit solvent systems with NPT and NVT ensemble. MD simulations uncovered dynamic behavior of 2-amino-3-pyridoxime-(Arg-Asn) and exposed its mobile nature and competence to form strong long range-order contacts towards active site residues to approach inhibited serine residue and facilitated via large contribution from hydrogen bonding and water bridges along with slow and large movements of adjacent important residues. In an effort to evaluate the complete potential surface profile, 2-amino-3-pyridoxime induced reactivation pathway of sarin-serine adduct has been investigated by the DFT approach at the vacuum MO6/6-311G (d, p) level along with the Poisson-Boltzmann solvation model and found to be of relatively low energy barrier. The pKa evaluation has revealed the major deprotonated 2-amino-3-pyridoixime species having pKa of 6.47 and hence making 2-amino-3-pyridoxime-(Arg-Asn) potential anticholinesterase and reactivator for AChE under the physiological pH.

A new SiF-Dipropargyl glycerol scaffold as a versatile prosthetic group to design dimeric radioligands: synthesis of the [(18) F]BMPPSiF tracer to image serotonin receptors.

A novel SiX-dipropargyl glycerol scaffold (X: H, F, or (18) F) was developed as a versatile prosthetic group that provides technical advantages for the preparation of dimeric radioligands based on silicon fluoride acceptor pre- or post-labeling with fluorine-18. Rapid conjugation with the prosthetic group takes place in microwave-assisted click conjugation under mild conditions. Thus, a bivalent homodimeric SiX-dipropargyl glycerol derivatized radioligand, [(18) F]BMPPSiF, with enhanced affinity was developed by using click conjugation. High uptake of the radioligand was demonstrated in 5-HT1A receptor-rich regions in the brain with positron emission tomography. Molecular docking studies (rigid protein-flexible ligand) of BMPPSiF and known antagonists (WAY-100635, MPPF, and MefWAY) with monomeric, dimeric, and multimeric 5-HT1A receptor models were performed, with the highest G score obtained for docked BMPPSiF: -6.766 as compared with all three antagonists on the monomeric model. Multimeric induced-fit docking was also performed to visualize the comparable mode of binding under in vivo conditions, and a notably improved G score of -8.455 was observed for BMPPSiF. These data directly correlate the high binding potential of BMPPSiF with the bivalent binding mode obtained in the biological studies. The present study warrants wide application of the SiX-dipropargyl glycerol prosthetic group in the development of ligands for imaging with enhanced affinity markers for specific targeting based on peptides, nucleosides, and lipids.

Synthesis, biological evaluation and molecular docking studies of high-affinity bone targeting N,N(') -bis (alendronate) diethylenetriamene-N,N'-triacetic acid: a bifunctional bone scintigraphy agent.

A bisphosphonate derivative DTPA-bis(alendronate) conjugate has been synthesized and evaluated as potential radiopharmaceutical for bone imaging. The compound was synthesized by the covalent coupling of DTPA-bis(anhydride) with alendronate and was char-acterized on the basis of IR, NMR and mass spectroscopy. It was labelled with (99m) Tc with 96% efficacy and was found stable for about 24 h under physiological conditions. Blood kinetic studies of (99m) Tc DTPA-bis(alendronate) showed a biexponential pattern as well as quick washout from the blood circulation. The biological t1/2 (F) and t1/2 (S) were found to be 50 min ± 0.001 and 6 h 30 min ± 0.005, respectively. Imaging and biodistribution studies showed a significant accumulation of (99m) Tc DTPA-bis(alendronate) conjugate at bone site. Bone-to-muscles ratios were 12.08 ± 0.001 at 1 h, 45.33 ± 0.001 at 4 h and 35.83 ± 0.001 at 24 h after post-injection, respectively. The receptor binding of the (99m) Tc-DTPA-bis (alendronate) was established on human bone cell line (Soas-2) revealed KD = 0.86 nm. The preliminary result of the (99m) Tc-DTPA-bis(alendronate) is encouraging to carrying out further in vivo experiment for targeted bone imaging because of good-bone-to-normal-organ contrast. Further docking analysis with molecular targets, farnesyl diphosphate synthase, geranylgeranyl pyrophosphate and osteocalcin revealed the high affinity of -17.419 and thus represents strong potential of bone-imaging agent.

Synthesis and biological evaluation of newly designed phosphonate based bone-seeking agent.

A cyclic tetraaza based bifunctional triphosphonate ligand 10-(2-aminoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tris(methylenephosphonic acid) (DO3MP-EA) was synthesized as bone-seeking theranostic agent. The compound was characterized by spectroscopic techniques and labelled with (99m)Tc with more than 97% purity. Blood clearance of 99mTc labelled compound a quick wash out from the circulation. The compound was excreted mainly via kidneys and accumulation of (99m)Tc-DO3MP-EA in bone was 9.53 ± 1.06% of injected dose per gram of bone at 1 h. The preliminary CADD analysis confirms the efficacy of DO3MP-EA (G Score -7.005) as better binding agent for osteocalcin (pdb 1Q8H) rather than other known clinical agents. Subsequently stability constant of chelate with Ga(III) was found to be 18.6 which confirms its efficacy as (68)Ga labelled PET radiopharmaceutical for bone.

Investigation for the interaction of tyramine-based anthraquinone analogue with human serum albumin by optical spectroscopic technique.

A newly synthesized anthraquinone derivative 'N-(2-methylanthraquinone)-4-(2-aminoethyl) phenol' (Tyan) were characterized as a fluorophore from photophysical analysis by measuring the UV-Vis absorptive (λ(ex) = 325 nm) and fluorescence emitive (λ(em) = 660 nm) values. Density functional theory additionally supported the spectroscopic data by modulation of highest occupied molecular orbital rather than lowest unoccupied molecular orbital due to the affect of tyramine moiety present in Tyan. The pharmacological importance of Tyan was evaluated by molecular docking with human serum albumin. The molecular docking of the Tyan was performed with the crystal structure of human serum albumin (PDB entry 1E78), which shows binding in all the three domains of human serum albumin corresponding to -7.74 as the GScore. Moreover, the interactions of human serum albumin with Tyan were assessed employing fluorescence spectroscopy under simulative physiological conditions, and the binding constant for the interaction at 25 °C was found to be 0.6 × 10(3)/M.