Current Computer - Aided Drug Design - Volume 14, Issue 2, 2018

Introduction: Sickle cell disease is characterized by a point mutation involving substitution of glutamic acid at position 6 to valine. Encoded in this hydrophobic mutation is both an intrinsic capacity for the beta globin molecules to assemble into thermodynamically favoured polymeric states as well as a rational way of interrupting the aggregation. Methods: In this work, starting with a theoretical model that employs occlusive binding onto the beta globin aggregation surface and using a range of computational methods and an effective energy for screening, a number of FDA approved drugs with computed aggregation inhibitory activities were identified. Results and Conclusion: The validity of the model was confirmed using sickling tests, after which pharmacophore models as well the structural basis for the observed antisickling effects were identified.

Background: Cytosolic Phospholipase A2 (cPLA2), an important isoform of PLA2 that mediates the release of arachidonic acid, plays a role in the pathogenesis of Spinal Cord Injury (SCI). The expression and activation of Cpla2 are significantly higher in SCI, leading to neuronal death in spinal cord tissue. Novel strategies are needed to substantially reverse the effect of cPLA2 activation; one such strategy is inhibiting cPLA2 by jamming its lipid binding C2 domain. Objective: To develop a much needed strategy to treat SCI, we used a Computer Aided Drug Design (CADD) method to discover novel cPLA2 inhibitors. Methods: we used a natural chemiome database for virtual screening, from which we selected the compounds exhibiting the greatest drug-likeliness properties for molecular docking simulation analysis. Results: We studied the interaction of lead compounds at the atomic level; the results yielded a cPLA2 inhibitor of natural origin with the potential for ameliorating secondary tissue damage and promoting recovery of function after SCI. The top compound, lead 4exibited a binding energy of -10.02 Kcal/mol and formed three hydrogen bonds with the lipid binding C2 domain of the cPLA2 protein. An evaluation of cell cytotoxicity revealed an IC50 for lead4 of 134.2 ± 6.8 μM. An in-vitro analysis of lead4 is indicated anti-apoptotic activity via a decrease in caspase-3 expression. Conclusion: We used the CADD method to make a novel lead discovery for the treatment of SCI using compounds of natural origin. The selected natural compounds are non-toxic promising drugs against cPLA2 protein, allowing us to limits our focus on single compound for future in-vitro and invivo testing.

Background: Transthyretin (TTR) is the transporter protein (55 kDa) that carries retinolbinding protein and Thyroxin (T4) in its functional tetramer form. Presence of the mutation in this protein (TTR) may lead to the dissociation of tetramers to monomer which unfolds and self-associates to form amyloid aggregates. Aggregation of this protein has been found to be associated with various lifethreatening disorders such as Coronary Artery Disease (CAD) which is the major cause of mortality and morbidity worldwide. Methods: In the present communication, we have predicted mutation prone residues of TTR with the help of suspect server. Substitution (T139R with 95 score) occurring at the thyroid hormone binding site was selected for studying the mutational consequences on TTR. The effect of mutation on stability, functionality, aggregation and folding rate was analyzed by MuPro, DUET, SDM, SNAP2, Polyphen2, PASTA2.0, Aggrescan and Folding RaCe servers. The presence of TTR monomer in CAD plasma has been observed through Western blot analysis. Results: T139R mutation may expose the buried regions of TTR protein which help in the self association and the increase in the stability may help in the TTR deposition. Structural analysis indicated that F and H strands of TTR are more prone to aggregation. Thus, T139R mutation might cause these residues to be aggregation prone and change in folding rate and validated TTR monomer in diseased cases by Western blot analysis. Conclusion: The observed results clearly indicated that the occurrence of this mutation is causing the impact on the structural and functional significance of TTR by interfering in the formation of tetramer. Thus, hindrance created to thyroxin transportation resulted in higher lipid levels in the blood that ultimately might promote the progression of the CAD.

Background: Leishmaniasis, malaria, and fungal diseases are burdens on individuals and populations and can present severe complications. Easily accessible chemical treatments for these diseases are increasingly sought-after. Targeting the parasite N-myristoyl transferase while avoiding the human enzyme and other anti-targets may allow the prospect of compounds with pan-activity against these diseases, which would simplify treatments and costs. Developing chemical libraries, both virtual and physical, that have been filtered and flagged early on in the drug discovery process (before virtual screening) could reduce attrition rates of compounds being developed and failing late in development stages due to problems of side-effects or toxicity. Methods: Chemical libraries have been screened against the anti-targets pregnane-X-receptor, sulfotransferase, cytochrome P450 2a6, 2c9, and 3a4 with three different docking programs. Statistically significant differences are observed in their interactions with these enzymes as compared to small molecule drugs and bioactive non-drug datasets. Results and Conclusion: A series of compounds are proposed with the best predicted profiles for inhibition of all parasite targets while sparing the human form and anti-targets. Some of the topranked compounds have confirmed experimental activity against Leishmania, and highlighted are those compounds with best properties for further development.

Background: Diabetes mellitus is a major worldwide health concern that has several serious complications including retinopathy, neuropathy, nephropathy and macrovascular diseases. Objective: Dipeptidyl peptidase-IV (DPP-IV) inhibitors, gliptins, are a new class of antidiabetic agents that potentiate the action of incretins in decreasing the blood glucose levels. Methods: In the present study, synthesis and characterization of a series of ten N4-sulfonamido-acrylic and phthalamic acid methyl esters (3a-e and 5a-e) were achieved. Results: In vitro anti-DPP-IV activity of the synthesized compounds was evaluated, where compound 3b demonstrated the best activity with a % inhibition of 41.7 at 10 μM concentration and an IC50 of 23.9 μM. Moreover, Glide docking experiments revealed that our targeted compounds accommodate the binding site of DPP-IV and tend to form H-bonding with the backbones of R125, E206, S209, D545, K554, W629, Y631, and G632. Conclusion: Modeling findings recommend the attachment of bulky hydrophobic group on the ester side of the structure in addition to harboring extra aromatic rings that might be beneficial for better binding interaction and biological activity.

Background: Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS) that imposes a global health burden. Therefore, HIV therapeutic agents have been discovery and development. Objective: To construct Quantitative-structure Activity Relationship (QSAR) models of betulinic acid derivatives with anti-HIV activity using Simplified Molecular-Input Line-Entry System (SMILES)- based descriptors. Methods: A data set of 107 betulinic acid derivatives and their anti-HIV activity was used to develop QSAR models. The SMILES format of the compounds was employed as descriptors for model construction using the CORAL software by means of the Monte Carlo method. Results: Constructed QSAR models provided good correlation coefficients (R2) and root mean square error (RMSE) with values in the range of 0.5660-0.5890 and 0.963-1.020, respectively, for the training set, R2 value of 0.7206-0.7837 and RMSE as 0.609-1.250, respectively, for the calibration set, and R2 value of 0.6257-0.7748 and RMSE as 0.837-0.995, respectively, for the validation set. The best QSAR model displayed statistical parameters for training set: R2 = 0.5660 and RMSE = 0.963; calibration set: R2 = 0.7273 and RMSE = 0.609, and validation set: R2 = 0.7748 and RMSE = 0.972. In addition, features of the molecular structure that are promoters of the endpoint increase and decrease were defined and discussed. These are the basis for the mechanistic interpretation of the suggested models. Conclusion: These findings provide useful knowledge for guiding the design of novel compounds with promising anti-HIV activity.

Background: Secreted Frizzled-Related Protein 4 (SFRP4) is a glycoprotein that acts as a competitor of both canonical and non-canonical Wnt pathways. SFRP4 is mostly expressed in ovary and plays a significant role as a target molecule to cure ovarian carcinoma. Objective: Multiple chemical agonists are being used to cure ovary melanoma. We are interested in theoretically analyzing the compounds through computational approaches for their potential inhibitory effects against SFRP4. Methods: Compounds were sketched in Chemsketch drawing tool and minimized through chimera tool. Because the crystal structure of SFRP4 is not available in Protein Data Bank, homology modeling approach was used to predict Three-Dimensional (3D) crystal structure of SFRP4. Moreover, multiple computational approaches such as molecular docking and Molecular Dynamic (MD) simulations along with various online tools were employed to screen the best inhibitor against ovary melanoma. Results: The docking results showed that 1d and 1e compounds revealed significant binding energy values (-9.10 and -9.00 kcal/mol, respectively) compared with the standard drugs such as cis-platin and docetaxel (-3.30, -10.80 kcal/mol), respectively. Moreover, MD simulation results showed that 1d has little fluctuations throughout the simulation period as depicted by the root mean square deviation and root mean square fluctuation graphs. Conclusion: The present in-silico study provides a deeper insight into the structural attributes of 1d compound and its overall molecular interactions against SFRP4 and gives a hypothetical gateway to use this compound as a potential inhibitor against ovarian carcinoma.