In-silico design of novel 4-aminoquinolinyl analogs as potential anti-malaria agents using quantitative structure– activity relationships and ADMET approach

Purpose: To design and screen for potential anti-malaria agents based on a series of 4-aminoquinolinyl analogues.Methods: Molecular fingerprint analysis was used for molecular partitioning of training and test sets. Acquired training sets were used for CoMFA and CoMSIA model construction after good alignment was achieved. Partial least squares analysis combined with external validation were used for  model evaluation. Deep analysis of acquired contour maps was performed to summarize the substituent property requirements for further rational molecular design. Using the chosen models, activity prediction and subsequent ADMET investigation were performed to discover novel designed  compounds with the desired properties.Results: Three different set partitions for model establishment were obtained using fingerprint-based selection. Partition 02 offered an optimal CoMFA model (r2 = 0.964, q2 = 0.605 and r2pred = 0.6362) and the best CoMSIA model (r2 = 0.955, q2 = 0.585 and r2 pred = 0.6403). Based on contour map analysis, a series of compounds were designed for activity prediction. Two of the compounds (wmx09, wmx25) were chosen for their ideal predicted biological activities. Subsequent ADMET investigation indicated that these compoundss have acceptable drug-like characteristics.Conclusion: The screening reveals that compounds wmx09 and wmx25 have strong potential as antimalaria agents. Keywords: Malaria, 4-Aminoquinolinyl, Molecular fingerprint, QSAR, ADME

Multi-Material Stereolithography: Spatially-Controlled Bioactive Poly(Ethylene Glycol) Scaffolds for Tissue Engineering

Challenges remain in tissue engineering to control the spatial and temporal mechanical and biochemical architectures of scaffolds. Unique capabilities of stereolithography (SL) for fabricating multi-material spatially-controlled bioactive scaffolds were explored in this work. To accomplish multi-material builds with implantable materials, a new mini-vat setup was designed, constructed and placed on top of the existing build platform to allow for accurate and selfaligning X-Y registration during fabrication. Precise quantities of photocrosslinkable solution were added to and removed from the mini-vat using micro-pipettes. The mini-vat setup allowed the part to be easily removed and rinsed and different photocrosslinkable solutions could be easily removed and added to the vat to aid in multi-material fabrication. Two photocrosslinkable hydrogel biopolymers, poly(ethylene glycol dimethacrylate) (PEG-dma, molecular wt 1,000) and poly(ethylene glycol)-diacrylate (PEG-da, molecular wt 3,400), were used as the primary scaffold materials, and controlled concentrations of fluorescently labeled dextran or bioactive PEG were prescribed and fabricated in different regions of the scaffold using SL. The equilibrium swelling behavior of the two biopolymers after SL fabrication was determined and used to design constructs with the specified dimensions at the swollen state. Two methods were used to measure the spatial gradients enabled by this process with multi-material spatial control successfully demonstrated down to 500-µm. First, the presence of the fluorescent component in specific regions of the scaffold was analyzed with fluorescent microscopy. Second, human dermal fibroblast cells were seeded on top of the fabricated scaffolds with selective bioactivity, and phase contrast microscopy images were used to show specific localization of cells in the regions patterned with bioactive PEG. The use of multi-material SL and the relative ease of conjugating different bioactive ligands or growth factors to PEG allows for the fabrication of tailored three-dimensional constructs with specified spatially-controlled bioactivity.Mechanical Engineerin

Design of Novel Anticancer Drugs Utilizing Busulfan for Optimizing Pharmacological Properties and Pattern Recognition Techniques for Elucidation of Clinical Efficacy

Chronic myelogenous leukemia (CML) is a disorder in which an excessive number of blood stem cells develop into the white blood cell group called granulocytes. The anticancer drug Busulfan is a cell cycle non-specific alkylating agent which is utilized to maintain white blood cell counts below 15000 cells/microliter. The side effects induced by busulfan are significant and affirms the intimation for new drug constructs. Fifteen analogous compounds were generated from the molecular structure of busulfan . These compounds retain the double methanesulfonate functional groups descriptive of this class of alkylating anticancer drugs. However, the carbon chain substituent separating the methanesulfonate is highly modified in order to allow significant changes in drug properties that may produce favorable characteristics that benefit clinical application. Important properties such as Log P, polar surface area, formula weight, molecular volume, Log BB, and violations of the Rule of 5 were determined to ascertain similarities and differences. All fifteen analog compounds retained zero violations of the Rule of 5, which suggests favorable properties for useful drug availability. Values of Log BB and BB remained the same throughout at -0.841 and 0.144, respectively. In addition, values of polar surface area and number of oxygens and nitrogens remained the same throughout at 86.752 A3 and 6, respectively. However, formula weight, number of atoms, number of rotatable bonds varied significantly with Log P varying across a broad range (-0.428 to 2.734). The variance in Log P within this group of methane sulfonate compounds allows new and potentially highly beneficial pharmacological properties for clinical application. Pattern recognition techniques such as cluster analysis, non-metric multidimensional scaling, discriminant analysis, and K-means cluster analysis discerned underlying relationships within this group of anticancer drugs and to the parent busulfan. This work shows that pattern recognition methods combined with molecular modeling can discover and elucidate novel drug designs for the clinical treatment of CML

Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design

β-Secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-β peptides, is an attractive target for the treatment of Alzheimer’s disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of nonpeptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC50 of 323 μM to 27 μM following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity. This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors

Novel, male-produced aggregation pheromone of the cerambycid beetle Rosalia alpina, a priority species of European conservation concern.

Several recent studies have demonstrated the great potential for exploiting semiochemicals in ecology and conservation studies. The cerambycid beetle Rosalia alpina represents one of the flagship species of saproxylic insect biodiversity in Europe. In recent years its populations appear to have declined substantially, and its range has shrunk considerably as a result of forest management and urbanization. Here, we collected volatile chemicals released by males and females of R. alpina. Analyses of the resulting extracts revealed the presence of a single male-specific compound, identified as a novel alkylated pyrone structure. In field bioassays in Slovenia, traps baited with the synthesized pyrone captured both sexes of R. alpina, indicating that the pyrone functions as an aggregation pheromone. Our results represent the first example of a new structural class of pheromones within the Cerambycidae, and demonstrate that pheromone-baited traps can provide a useful tool for sampling R. alpina. This tool could be particularly useful in the ongoing development of conservation strategies for the iconic but endangered Alpine longicorn

Using Chemical Biology to Modulate Antibody Activity

Monoclonal antibodies have shown promising results as therapeutic agents, and yet they can also be associated with adverse side effects due to activity outside the disease site. Aiming to reduce these side effects, we have explored the possibility of a tunable antibody, whose activity can be manipulated via the addition of a small molecule. Previously, we incorporated a single cavity-forming mutation (tryptophan to glycine) into an antibody, and observed reduced antigen-binding activity that could be restored by addition of a complementary ligand (indole) — albeit with binding affinity too low for potential therapeutic applications. Here, I describe a novel computational strategy for enumerating larger cavities in a fluorescein-binding single-chain variable fragment (scFv), leading to a designed variant with three large-to-small mutations (triple mutant) at the domain-domain interface with reduced antigen-binding. Through a complementary virtual screen, we identified a rescuing small molecule (JK43) that enhances binding affinity for antigen. Thorough characterization of this system shows that the loss of activity upon mutation was due to loss of stability and domain dissociation; conversely, addition of JK43 restores stability of the antibody fragment, induces domain re-association, and rescues antigen binding. Beyond this initial model system, I will also describe the transferability of this design (triple mutant and JK43) from the fluorescein-binding scFv onto an unrelated scFv that shares the same three residues used in this design. We hypothesize that this design will also prove transferable onto the many therapeutic antibodies that also share these three residues, including Ipilimumab (anti-CTLA-4), Atezolimumab (anti-PD-L1), Nivolumab (anti-PD-1) and Adalimumab (anti-TNF-α)

Drug design: hiding in full view

Compounds that can produce potent biological effects in cells encompass a variety of structural motifs. Many of these compounds share a structural feature that has rarely been noted. It is an allylic cluster of atoms, a 3-carbon chain with a double bond between two of the atoms and an oxygen atom at the other end. The oxygen can be in a hydroxyl group, or in an ether or ketal or ester linkage, or simply a carbonyl form. In the latter case, the linkage is an allylic ketone (ene-one) structure. Nitrogen is often seen in equivalent forms. Inclusion of at least one allylic moiety appears to be able to turn a modestly active or inert compound into an effective drug or toxin. Some compounds lack the allylic moiety but develop one by enzymatic action, usually via cytochrome P-450 enzymes. These metabolites probably represent the active drug forms. The above concepts seem to be radically simplistic and improbable, but the evidence supporting them and the explanations for the biological activities are hidden “in plain view.” Comparisons with the pleiotropic activities of the allylic sphingolipid, ceramide, indicate that many allylic drugs operate by controlling the state of protein phosphorylation, by activating proteases, by generating reactive oxygen species, by slowing mitochondrial electron transport, or by lowering cellular glutathione concentrations. Drug Dev Res 69:15–25, 2008 © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58639/1/20223_ftp.pd