Hyphenated 3D-QSAR statistical model-drug repurposing analysis for the identification of potent neuraminidase inhibitor

Abstract

The Influenza A virus is one of the principle causes of respiratory illness in human. The surface glycoprotein of the influenza virus, neuraminidase (NA), has a vital role in the release of new viral particle and spreads infection in the respiratory tract. It has been long recognized as a valid drug target for influenza A virus infection. Oseltamivir is used as a standard drug of choice for the treatment of influenza. However, the emergence of mutants with novel mutations has increased the resistance to potent NA inhibitor. In the present investigation, we have employed computer-assisted combinatorial techniques in the screening of 8621 molecules from Drug Bank to find potent NA inhibitors. A three-dimensional pharmacophore model was generated from the previously reported 28 carbocylic influenza NA inhibitors along with oseltamivir using PHASE module of Schrödinger Suite. The model generated consists of one hydrogen bond acceptor (A), one hydrogen bond donors (D), one hydrophobic group (H), and one positively charged group (P), ADHP. The hypothesis was further validated for its integrity and significance using enrichment analysis. Subsequently, an atom-based 3D-QSAR model was built using the common pharmacophore hypothesis (CPH). The developed 3D-QSAR model was found to be statistically significant with R value of 0.9866 and Q value of 0.7629. Further screening was accomplished using three-stage docking process using the Glide algorithm. The resultant lead molecules were examined for its drug-like properties using the Qikprop algorithm. Finally, the calculated pIC values of the lead compounds were validated by the AutoQSAR algorithm. Overall, the results from our analysis highlights that lisinopril (DB00722) is predicted to bind better with NA than currently approved drug. In addition, it has the best match in binding geometry conformations with the existing NA inhibitor. Note that the antiviral activity of lisinopril is reported in the literature. However, our paper is the first report on lisinopril activity against influenza A virus infection. These results are envisioned to help design the novel NA inhibitors with an increased antiviral efficacy.

Design and Synthesis of Novel Oxime Ester Photoinitiators Augmented by Automated Machine Learning

“…Recently, there has been a breakthrough in automating and streamlining computerized algorithms for the generation and ranking of predictive regression models, which comprise the best-practice workflow for standard quantitative structure–property relationship (QSPR)-based property predictions in a modularized form of the software package . It has greatly expanded the accessibility of standardized “machine learning for chemistry” in pharmaceutical and other life science applications. − However, the same principle has not been widely tested and validated in materials chemistry where successful high-throughput virtual screening could also pay a huge dividend. By the nature of operating mechanisms, which implies a strong correlation between chemical design space and the product performance, development of new photoinitiators for a wide variety of photochemical applications − is one of such areas that can readily take the benefit of the chemistry-based machine learning methods.…”

Discovery of Potent Covid-19 Main Protease Inhibitors Using Machine Learning Based Virtual Screening Strategy

“…In this process the hits were ranked using a three step hierarchical process, viz HTVS, SP and XP. The use of such hierarchical filters and associated parameters were highlighted in our earlier articles [18,29,30]. Initially, HTVS was carried out and 500 (50%) of the high scoring compounds were selected for the SP docking.…”

Peptides as epigenetic modulators: therapeutic implications

“…Several approved peptide drugs are already being repositioned to other indications. For example, lisinopril, a synthetic tripeptide derivative approved for treatment of hypertension and heart failure, binds strongly to neuraminidase and has antiviral activity against influenza A [169]. Glatiramer, approved for the treatment of multiple sclerosis, shows promising effects in Huntington’s disease and as an antibiotic [170, 171] and liraglutide against obesity, non-alcoholic fatty liver disease, and depression [172, 173].…”