Current Computer - Aided Drug Design - Volume 14, Issue 3, 2018

There has been a rapid surge in the research and exchange of ideas in various areas of chemistry such as organic, pharmaceutical, analytical, and medicinal chemistry. It is well recognized that heterocycles are vital components of many biochemical processes. Pharma industry comprises more than 75% of top selling drugs that are of heterocyclic origin. Among many diseases, cancer can be considered to be a dreaded disease that has overtaken the masses across the globe. Hence, there has been a need to develop drugs that are less toxic and do not provide resistance in the long run. Thus, this need-based development of anticancer drugs through the use of heterocycles has gained its pace since last two decades and there has been a gush among the researchers to apply various approaches in designing anticancer molecules. More specifically, research is being targeted on the utilization of molecular modeling techniques for developing new anticancer agents specifically targeting various cancer cell lines, specific enzymes and tissues. Some of the important and conclusive findings using this approach have been presented in this review.

Background: Melanoma is the most aggressive type of skin cancer. Metastatic melanoma is extremely difficult to treat with current therapy methods such as surgery. On the other hand, it is a good opportunity to develop a radiopharmaceutical using a radionuclide such as Technetium (Tc) for diagnostic and Rhenium (Re) for therapeutic purposes. T3,4BCPP has been be used as a radioimaging agent for melanoma cancers experimentally. The aim of the present research was to design new imidazolylporphyrin derivatives with better selectivity and higher affinity than those of T3,4BCPP by molecular modeling. Methods: Eight types of Re- and Tc-labeled imidazolylporphyrins were docked to Fibroblast Growth Factor Receptor 1 (FGFR1, PDB ID: 5AM6) using AutoDock 4.2. FGFR1 was simulated by Molecular Dynamic (MD) simulation for 30 ns using NAMD 2.10 at 37 °C. The obtained conformations were then applied in a molecular docking simulation. Dovitinib (natural ligand of FGFR1), Re- and Tc-T3, 4BCPP were used as references. Results: The MD simulation resulted in an RMSD of 3.8 Ů From all the studied imidazolylporphyrin derivatives, Tc-cD3, 4BCPMIP and Re-cD3, 4BCPIP had the best docking parameter. Tc-cD3, 4BCPMIP had a free binding energy of -4.06 kcal/mol, while that of Re-cD3, 4BCPIP was -4.35 kcal/mol. Conclusion: It is concluded that cD3,4BCPMIP and cD3,4BCPIP are two potential candidate ligands for a melanoma radiopharmaceutical kit.

Introduction: Morbidity and mortality due to tuberculosis are rising steadily. Despite having efficient drugs and treatment protocols, microbial drug resistance often leads to treatment failure. Efforts to bring novel drugs to combat this menace are hampered by several issues including problems in gaining industry support, motivation and ethical issues clinical trials. Bedaquiline and Delaminid are the only novel drugs approved in the last three decades for treating TB. A few more molecules and drug combinations are still in clinical trials. One such drug is the BM212, a potent anti-TB agent which acts by a novel mechanism of action. Methods: In the present study, we used virtual screening method with a combination of molecular hybridization technique to design N-benzylated Indole Mannich bases as potent anti-TB agent based on BM212 pharmacophore. The library of designed molecules was prepared and screened using BM212 model. The top 5 ‘hit’ molecules were selected (with good TC score >1.15), synthesized and screened for anti TB activity by MABA assay method. Results and Conclusion: All the compounds showed excellent anti TB activity, of which 4 compounds have shown MIC ≤12.5 μg/mL. Our protocol could help in the designing of newer anti-TB agents with better bioactivity profile.

Introduction: In this paper, we have introduced a new atomic descriptor with Klopman index to determine the local reactive sites of the molecular systems during electrophilic, and nucleophilic attacks. This index, similar to other local reactivity descriptors but more advanced, has been used as a realistic descriptor to discover new aspects of molecular structure. Methods: Nonlinear Least Squares (NLLS) methods to define the parameters maximizing the fit between the observed points and the computed simulation results were performed according to the Levenberg- Marquardt (LM) algorithm. We have attempted to demonstrate the structural properties of compounds that contribute not only basic pharmacophore (b-Pha) but also positive (Auxiliary Group- AG) or negative (Anti-Pharmacophore Shielding-APS) due to the new local atomic reactivity. Results and Conclusion: In the 4D-QSAR study, nonparametric regression analysis was used to determine the adjustable constants. Using the leave One Out Cross-Validation (LOO-CV), antibacterial activities (pEC50-μM) were predicted as r2 loo-cv (q2) = 0.979, r2 pred (r2) = 0.911, respectively, for 27 training sets and 9 test set compounds. Also, the rm2(overall) value, which indicates the closeness between the predicted and corresponding observed data, was calculated to be 0.957. The model obtained by the Molecular Conformer Electron Topological (MCET) method was compared with the q2 loo-cv and R2 non-cv values determined by the CoMFA and CoMSIA methods and more satisfactory results were obtained.

Introduction: In the present research work, a pharmacophore based virtual screening was performed using Discovery Studio 2.1 for the discovery of some novel molecules as inhibitors of Squalene Synthase Enzyme, a key enzyme in cholesterol biosynthetic pathway. Methods: A quantitative pharmacophore HypoGen was generated and the best HypoGen had two ring aromatic and one hydrogen bond acceptor lipid features. The best HypoGen showed a very good correlation coefficient (r = 0.901) with satisfactory cost analysis. Furthermore, the HypoGen was validated externally by predicting the activity of test set. The developed model was found to be predictive as it showed low error of prediction for test set molecules. The developed model was used as a search query for virtually screening two chemical databases: sample database from catalyst and minimaybridge. Results and Discussion: The best hit with good fit value and low predicted activity was further modified to design novel drug-like molecules, which were able to bind to Squalene synthase enzyme active site. Conclusion: The best scoring molecule, compound 67 showed 53% inhibition of the human Squalene synthase enzyme, isolated from the cell lysates of Human Hepatoma Cell Line, at a dose of 10 mcg with an IC50 value of 9.43 μm.

Background: Genus Isodon (Lamiaceae) is a prolific source for bioactive terpenoids. Nowadays, people move towards natural products because of undesirable effects of chemotherapeutic drugs. Objective: In silico and in vitro approaches were attempted to screen bioactive terpenoids isolated from Isodon wightii with acetylcholinesterase and histone deacetylase3 receptors. Methods: Terpenoids such as abietic acid, oleanolic acid, α-amyrin acetate, β-amyrin acetate were docked with AchE and HDAC3 receptors using AutoDock Vina (version 1.1.2). Further, GROMACS 5.1.2 package was used to perform molecular dynamic simulation. In vitro apoptosis was tested using hoechst 33258 and acridine orange/ethidium bromide. Results: Ligplot analysis indicated that abietic acid had strong binding efficiency with AchE and HDAC3 receptors forming one and four hydrogen bonds respectively. Root mean square deviation analysis showed AchE-abietic acid and HDAC3-abietic acid complexes with high deviation which later attains equilibrium around ~25000ps and ~10000ps respectively. Root mean square fluctuation study showed that the complexes have high fluctuations indicates the high flexibility of residues. Solvent accessible surface area revealed the favourable interacting region of AchE and HDAC3 receptors with abietic acid in the range of ~215nm2 to ~235nm2 and ~157nm2 to ~175nm2 respectively. Apoptosis inducing the activity of abietic acid was tested against HeLa cells. Hoechst 33258 staining showed increased apoptosis by abietic acid in a concentration-dependent manner. AO/EtBr dual staining showed early apoptosis at 25-75μg/mL and necrosis at 100-125μg/mL abietic acid. Conclusion: In silico and in vitro studies suggest that abietic acid could be a promising terpenoid for treating Alzheimer's disease and cervical cancer.

Background: Gefitinib (lressa) is the most prescribed drug, highly effective to treat nonsmall cell lung cancer; primarily it was considered that targeted therapy is a kinase inhibitor. The nonsmall cell lung cancer is caused by mutation in the Epithelial Growth Factor Receptor (EGFR) gene. Iressa works by blocking the EGFR protein that helps the cancer cell growth. EGFR protein has lead to the development of anticancer therapeutics directed against EGFR inhibitor including Gefitinib for non-small cell lung cancer. Methods: To explore the interaction between Gefitinib and its derivatives with crystal structure of EGFR to understand the better molecular insights interaction strategies. Molecular modeling of ligands (Gefitinib and its derivatives) was carried out by Avogadro software till atomic angle stable confirmation was obtained. The partial charges for the ligands were assigned as per standard protocol for molecular docking. All docking simulations were performed with AutoDockVina. Virtual screening was carried out based on binding energy and hydrogen bonding affinity. Molecular dynamics (MD) and Simulation EGFR were done using GROMACS 5.1.1 software to explore the interaction stability in a cell. Results: The stable conformation for EGFR protein trajectories were captured at various time intervals 0-20ns. Few compounds screen based on high affinity as the inhibitor for EGFR may inhibit the cell cycle signaling in non-small cell lung cancer. Conclusion: These result suggested a computer-aided screening approach of Gefitinib derivatives with regard to their binding to EGFR for identifying novel drugs for the treatment of non-small cell lung cancer.

Background: Drepanocytosis is a genetic blood disorder characterized by red blood cells that assume an abnormal, rigid, sickle shape. In the pathogenesis of vaso-occlusive crises of sickle cell disease, red blood cells bind to the endothelium and promote vaso-occlusion. At the surface of these sickle red blood cells, the overexpressed protein Lutheran strongly interacts with the Laminin 511/521. The aim of this study is to identify a PPI inhibitor with a high probability of binding to Lutheran for the inhibition of the Lutheran-Laminin 511/521 interaction. Methods: A virtual screening was performed with 395 601 compounds that target Lutheran. Prior validation of a robust docking and scoring protocol was considered on the protein CD80 because this protein has a binding site with similar topological and physico-chemical characteristics and it also has a series of ligands with known affinity constants. This protocol consisted of multiple filtering steps based on docked scores, molecular dynamics simulations, post-screening scores, and molecular properties. Results: A robust docking and scoring protocol was validated on the protein CD80 with the docking program DOCK6 and the secondary scoring function XSCORE. We identified four molecules for Lutheran that have good structural and physico-chemical properties. Conclusion: We took advantage of the similarities between the binding site of Lutheran and that of the protein CD80 to set up a robust docking and scoring protocol. Our protocol for primary scoring filtering, molecular dynamics simulation filtering, secondary scoring filtering, and molecular property filtering allows discarding most of the ligands with four compounds that are promising candidates for inhibiting the Lutheran-Laminin 511/521 interaction.