Anticancer Drug Discovery By Structure-Based Repositioning Approach.

Despite the tremendous progress that has occurred in recent years in cell biology and oncology, in chemical, physical and computer sciences, the disease cancer has continued as the major cause of death globally. Research organizations, academic institutions and pharmaceutical companies invest huge amounts of money in the discovery and development of new anticancer drugs. Though much effort is continuing and whatever available approaches are being attempted, the success of bringing one effective drug into the market has been uncertain. To overcome problems associated with drug discovery, several approaches are being attempted. One such approach has been the use of known, approved and marketed drugs to screen these for new indications, which have gained considerable interest. This approach is known in different terms as "drug repositioning or drug repurposing." Drug repositioning refers to the structure modification of the active molecule by synthesis, in vitro/ in vivo screening and in silico computational applications where macromolecular structure-based drug design (SBDD) is employed. In this perspective, we aimed to focus on the application of repositioning or repurposing of essential drug moieties present in drugs that are already used for the treatment of some diseases such as diabetes, human immunodeficiency virus (HIV) infection and inflammation as anticancer agents. This review thus covers the available literature where molecular modeling of drugs/enzyme inhibitors through SBDD is reported for antidiabetics, anti-HIV and inflammatory diseases, which are structurally modified and screened for anticancer activity using respective cell lines.

Fibroblast growth factor receptor (FGFR) inhibitors as anticancer agents: 3D-QSAR, molecular docking and dynamics simulation studies of 1, 6-naphthyridines and pyridopyrimidines.

Fibroblast growth factor receptor (FGFR) plays a vital role in tissue regeneration, angiogenesis, and embryogenesis. 3D-QSAR and molecular modeling methods are widely used for designing novel compounds for the determination of inhibitory activity against the biological target. In the present study, 3D-QSAR (CoMFA and CoMSIA) analysis was performed on 1, 6-naphthyridines, and pyridopyrimidines as potential FGFR inhibitors as anticancer agents. The best CoMFA and CoMSIA models were generated from test and training set derivatives with leave-one-out correlation coefficients (q2) 0.591 and 0.667, cross-validated correlation coefficients (r2cv) 0.584 and 0.652, conventional coefficients (r2ncv) 0.978 and 0.975 respectively. The developed models were validated by a test set of 12 compounds providing acceptable predictive correlation coefficient (r2pred) 0.61 and 0.68 for both models. The generated CoMFA and CoMSIA contour maps could be used to design novel 1, 6-naphthyridine analogs. Molecular docking studies indicated that compound 75 occupied the active site of the FGFR kinase interacting with Glu520 in the catalytic region, Asp630 in the DFG motif, and Met524 in the hinge region which compared with standard drug Ponatinib. The molecular dynamics simulation analysis revealed that the inhibitor 75 displayed binding stability in the active site of the FGFR4 by making two hydrogen bonds and one π-cation interaction. Collectively the outcome of the study suggested that the applications of ligand-based and structure-based approaches could be applied for the design of new FGFR4 inhibitors as anticancer agents.Communicated by Ramaswamy H. Sarma.

Lyotropic liquid crystals for parenteral drug delivery.

The necessity for long-term treatments of chronic diseases has encouraged the development of novel long-acting parenteral formulations intending to improve drug pharmacokinetics and therapeutic efficacy. Lately, one of the novel approaches has been developed based on lipid-based liquid crystals. The lyotropic liquid crystal (LLC) systems consist of amphiphilic molecules and are formed in presence of solvents with the most common types being cubic, hexagonal and lamellar mesophases. LC injectables have been recently developed based on polar lipids that spontaneously form liquid crystal nanoparticles in aqueous tissue environments to create the in-situ long-acting sustained-release depot to provide treatment efficacy over extended periods. In this manuscript, we have consolidated and summarized the various type of liquid crystals, recent formulation advancements, analytical evaluation, and therapeutic application of lyotropic liquid crystals in the field of parenteral sustained release drug delivery.

Therapeutic Approaches to Amyotrophic Lateral Sclerosis from the Lab to the Clinic.

Amyotrophic Lateral Sclerosis (ALS) is a terminal neuro-degenerative disorder that is clinically recognized as a gradual degeneration of the upper and lower motor neurons, with an average duration of 3 to 5 years from initial of symptoms to death. The mechanisms underlying the pathogenesis and progression of the disease are multifactorial. Therefore, to find effective treatments, it is necessary to understand the heterogeneity underlying the progression of ALS. Recent developments in gene therapy have opened a new avenue to treat this condition, especially for the characterized genetic types. Gene therapy methods have been studied in various pre-clinical settings and clinical trials, and they may be a promising path for developing an effective and safe ALS cure. A growing body of evidence demonstrates abnormalities in metabolic energy at the cellular and whole-body level in animal models and people living with ALS. Using and incorporatig high-throughput "omics" methods have radically transformed our thoughts about ALS, strengthened our understanding of the disease's dynamic molecular architecture, differentiated distinct patient subtypes, and created a reasonable basis for identifying biomarkers and novel individualised treatments. Future clinical and laboratory trials would also focus on the diverse relationships between metabolism and ALS to address the issue of whether targeting poor metabolism in ALS is an effective way to change disease progression. In this review, we focus on the detailed pathogenesis of ALS and highlight principal genes, i.e., SOD1, TDP-43, C9orf72, and FUS, as well as targeted ALS therapies. An attempt is made to provide up-to-date clinical outcomes, including various biomarkers that are thought to be important players in early ALS detection.

Advanced Computational Methodologies Used in the Discovery of New Natural Anticancer Compounds.

Natural chemical compounds have been widely investigated for their programmed necrosis causing characteristics. One of the conventional methods for screening such compounds is the use of concentrated plant extracts without isolation of active moieties for understanding pharmacological activity. For the last two decades, modern medicine has relied mainly on the isolation and purification of one or two complicated active and isomeric compounds. The idea of multi-target drugs has advanced rapidly and impressively from an innovative model when first proposed in the early 2000s to one of the popular trends for drug development in 2021. Alternatively, fragment-based drug discovery is also explored in identifying target-based drug discovery for potent natural anticancer agents which is based on well-defined fragments opposite to use of naturally occurring mixtures. This review summarizes the current key advancements in natural anticancer compounds; computer-assisted/fragment-based structural elucidation and a multi-target approach for the exploration of natural compounds.