Discovery of anaplastic lymphoma kinase inhibitors from natural product library: A holistic in silico approach.

Over the years, phytochemical compounds have shown compelling evidences in exhibiting powerful antitumor properties. Moreover, due to the lack of safety and high cost of cancer therapies, opportunities are being sought out in these compounds as an alternative treatment modality. Therefore, in the present study, 1,574 compounds from NPACT library were examined to excavate potent and nontoxic anaplastic lymphoma kinase (ALK) inhibitors. Notably, two pharmacophore hypotheses (AAAHP and DDRRR) were generated using ligand-based and energy-based techniques, respectively, to eliminate false-positive prediction in database screening. Furthermore, molecular docking and Prime MM/GBSA analysis were performed on the screened compounds to examine inhibitory activity against ALK. The analysis revealed that the two hits, namely, NPACT00018 and NPACT01077, exhibited better docking scores, binding energies, and also ensured excellent drug-likeness properties than the reference compound, crizotinib. Finally, the results were subjected to molecular dynamics studies to gain insight into the stability of these compounds in the binding pocket of ALK protein. Indeed, the useful predictions generated by the present computational models are of immense importance and could further speed up the anticancer drug development in the near future.

Density Functional Theory and Molecular Simulation Studies for Prioritizing Anaplastic Lymphoma Kinase Inhibitors.

Targeting anaplastic lymphoma kinase (ALK) is one of the important treatment strategies for the treatment of non-small cell lung cancer (NSCLC). In the present perspective, multidimensional approaches were used for the identification of ALK inhibitors. Initially, an e-pharmacophore model was generated using the PHASE algorithm and was used as a 3D query to screen 468,200 molecules of ASINEX database. Prior to the screening process, the model was evaluated for its significance and the ability to differentiate actives from inactives, using enrichment analysis. Subsequently, the hierarchical docking protocol and binding free energy calculations were instigated using GLIDE algorithm and Prime module, respectively. Further, the pharmacokinetic/pharmacodynamics (PK/PD) properties and toxicities of the hit compounds were envisaged respectively using QikProp program, Osiris explorer, and Protox-II algorithm. These approaches retrieved two hits namely BAS 00137817 and BAS 00680055 with acceptable absorption, distribution, metabolism, excretion and toxicity (ADMET) properties and higher affinity towards ALK protein. Additionally, density functional theory calculations and molecular dynamics simulations were performed to validate the inhibitory activity of the lead compounds. It is noteworthy to mention that all the hits constitute of particular scaffolds which play a major role in the downregulation of some ALK-positive lung cancer pathways. We speculate that the outcomes of this research are of substantial prominence in the rational designing of novel and efficacious ALK inhibitors.

Ligand-Based Pharmacophore Screening Strategy: a Pragmatic Approach for Targeting HER Proteins.

Targeting ErbB family of receptors is an important therapeutic option, because of its essential role in the broad spectrum of human cancers, including non-small cell lung cancer (NSCLC). Therefore, in the present work, considerable effort has been made to develop an inhibitor against HER family proteins, by combining the use of pharmacophore modelling, docking scoring functions, and ADME property analysis. Initially, a five-point pharmacophore model was developed using known HER family inhibitors. The generated model was then used as a query to screen a total of 468,880 compounds of three databases namely ZINC, ASINEX, and DrugBank. Subsequently, docking analysis was carried out to obtain hit molecules that could inhibit the HER receptors. Further, analysis of GLIDE scores and ADME properties resulted in one hit namely BAS01025917 with higher glide scores, increased CNS involvement, and good pharmaceutically relevant properties than reference ligand, afatinib. Furthermore, the inhibitory activity of the lead compounds was validated by performing molecular dynamic simulations. Of note, BAS01025917 was found to possess scaffolds with a broad spectrum of antitumor activity. We believe that this novel hit molecule can be further exploited for the development of a pan-HER inhibitor with low toxicity and greater potential.

Discovery of Potent ALK Inhibitors Using Pharmacophore-Informatics Strategy.

Anaplastic lymphoma kinase is a tyrosine kinase receptor protein belonging to insulin receptor superfamily. Gene fusions in anaplastic lymphoma kinase are associated with non-small cell lung cancer development. Hence, they are of immense importance in targeted therapies. Thus, for the treatment of non-small cell lung cancer, effective anaplastic lymphoma kinase inhibitors are of great significance. Therefore, our objective is to find hit compounds that could have better inhibitory activity than the existing anaplastic lymphoma kinase inhibitors. Keeping this in mind, in the present study pharmacophore based virtual screening was performed to identify possible anaplastic lymphoma kinase inhibitors. Initially, a five-point common pharmacophore hypothesis was generated based on twelve anaplastic lymphoma kinase inhibitors using PHASE module of Schrödinger. Subsequently, common pharmacophore hypothesis-based screening was conducted against in-trials subset of ZINC database and a total of 1000 hits were identified. The molecules obtained were further screened by three stages of docking using GLIDE software. The docking results reveal that six hit molecules showed higher glide score in comparison with the reference molecules. Finally, pharmacokinetic properties of the hit molecules were also analysed using QikProp programme. The results indicate that molecules namely videx, dexecadotril, chloramphenicol, naficillin were found to have good pharmacokinetic properties and human oral absorption. Moreover, videx, naficillin and chloramphenicol were found to have significant inhibitory activity for mutant (F1174L) anaplastic lymphoma kinase. It was also found that videx exhibited crucial interactions with the Met1199 residue of the native and mutant anaplastic lymphoma kinase protein. Furthermore, PASS algorithm predicted anti-neoplastic activity for all the four molecules. Thus these hits are found to be promising leads for anaplastic lymphoma kinase inhibitors. We believe that this study will be useful for the discovery and designing of more potent anaplastic lymphoma kinase inhibitors in the near future.

Drug Design for ALK-Positive NSCLC: an Integrated Pharmacophore-Based 3D QSAR and Virtual Screening Strategy.

The increasing death rates related to anaplastic lymphoma kinase (ALK)-positive lung cancer culminated in a significant interest in the discovery of novel inhibitors for ALK. In the present research work, pharmacophore-based 3D QSAR modeling and virtual screening strategy have been carried out to address these issues. Initially, a five-point pharmacophore model was developed using the biological data of 50 compounds which includes an FDA-approved ALK inhibitor, crizotinib. Using the generated pharmacophore, a 3D QSAR model was developed and used as a query to screen the DrugBank database. The model was found to be significant (R 2 = 0.9696) with an excellent predictive accuracy (Q 2 = 0.7652) as confirmed through validation of the both training and test molecule activities. Further, Glide docking score and absorption, distribution, metabolism and excretion properties were used to filter the screened candidates. Overall, our analysis results in three hits namely TR1, FAL, ZYW with higher docking scores, and good pharmaceutically relevant properties with increased CNS involvement. It is worth mentioning that FAL and ZYW were found to possess scaffolds with specific activity against ALK protein. We presume that the results obtained from this computational study are of immense importance in the rational designing of novel and more potent ALK inhibitors.