Understanding the stability and dynamics of influenza a H5N1 polymerase PB2 CAP-Binding domain in complex with natural compounds for antiviral drug discovery.

Influenza A virus, particularly the H5N1 strain, poses a significant threat to public health due to its ability to cause severe respiratory illness and its high mortality rate. Traditional antiviral drugs targeting influenza A virus have faced challenges such as drug resistance and limited efficacy. Therefore, new antiviral compounds are needed to be discovered and developed. This study concentrated on examining the stability and behavior of the H5N1 polymerase PB2 CAP-binding domain when interacting with natural compounds, aiming to identify potential candidates for antiviral drug discovery. Through the virtual screening process, four lead compounds, ZINC000096095464, ZINC000044404209, ZINC000001562130, and ZINC000059779788, were selected, and these compounds showed binding energies -9.6, -9.4, -9.3, and -9.2 kcal/mol, respectively. When complexed with PB2, the ligand showed acceptable binding stability due to significant bond formation. However, during the 200ns MD simulation analysis, three (ZINC000096095464, ZINC000044404209, and ZINC000059779788) showed significant stability, which was proven by the trajectory analysis. The Rg-RMSD-based FEL plot showed significant structural stability due to stable conformers. The free-binding energy calculation also validates the stability of these complexes. This study offers valuable insights into the stability and dynamics of the H5N1 polymerase PB2 CAP-binding domain in complexes with natural compounds. These findings highlight the potential of these natural compounds as antiviral agents against the H5N1 influenza virus. Furthermore, this research contributes to the broader field of influenza virus treatment by demonstrating the effectiveness of computational methods in predicting and evaluating the stability and dynamics of potential drug candidates.

Unravelling the role of microneedles in drug delivery: Principle, perspectives, and practices.

In recent year, the research of transdermal drug delivery systems has got substantial attention towards the development of microneedles (MNs). This shift has occurred due to multifaceted advantages of MNs as they can be utilized to deliver the drug deeper to the skin with minimal invasion, offer successful delivery of drugs and biomolecules that are susceptible to degradation in gastrointestinal tract (GIT), act as biosensors, and help in monitoring the level of biomarkers in the body. These can be fabricated into different types based on their applications as well as material for fabrication. Some of their types include solid MNs, hollow MNs, coated MNs, hydrogel forming MNs, and dissolving MNs. These MNs deliver the therapeutics via microchannels deeper into the skin. The coated and hollow MNs have been found successful. However, they suffer from poor drug loading and blocking of pores. In contrast, dissolving MNs offer high drug loading. These MNs have also been utilized to deliver vaccines and biologicals. They have also been used in cosmetics. The current review covers the different types of MNs, materials used in their fabrication, properties of MNs, and various case studies related to their role in delivering therapeutics, monitoring level of biomarkers/hormones in body such as insulin. Various patents and clinical trials related to MNs are also covered. Covered are the major bottlenecks associated with their clinical translation and potential future perspectives.

Towards the discovery of potential RdRp inhibitors for the treatment of COVID-19: structure guided virtual screening, computational ADME and molecular dynamics study.

Coronavirus disease 2019 (COVID-19) has become a major challenge affecting almost every corner of the world, with more than five million deaths worldwide. Despite several efforts, no drug or vaccine has shown the potential to check the ever-mutating SARS-COV-2. The emergence of novel variants is a major concern increasing the need for the discovery of novel therapeutics for the management of this pandemic. Out of several potential drug targets such as S protein, human ACE2, TMPRSS2 (transmembrane protease serine 2), 3CLpro, RdRp, and PLpro (papain-like protease), RNA-dependent RNA polymerase (RdRP) is a vital enzyme for viral RNA replication in the mammalian host cell and is one of the legitimate targets for the development of therapeutics against this disease. In this study, we have performed structure-based virtual screening to identify potential hit compounds against RdRp using molecular docking of a commercially available small molecule library of structurally diverse and drug-like molecules. Since non-optimal ADME properties create hurdles in the clinical development of drugs, we performed detailed in silico ADMET prediction to facilitate the selection of compounds for further studies. The results from the ADMET study indicated that most of the hit compounds had optimal properties. Moreover, to explore the conformational dynamics of protein-ligand interaction, we have performed an atomistic molecular dynamics simulation which indicated a stable interaction throughout the simulation period. We believe that the current findings may assist in the discovery of drug candidates against SARS-CoV-2.