Applications of QSAR study in drug design of tubulin binding inhibitors.

New drug discovery is recognized as a complicated, costly, time-consuming, and difficult process. Computer-aided drug discovery has developed as a potent and promising method for faster, cheaper, and more effective drug creation. Recently, the rapid rise of computational methods for drug discovery, including anticancer medicines, had a substantial and exceptional impact on anticancer drug design, as well as providing beneficial insights into the field of cancer therapy. In this paper, we discussed the quantitative structure-activity relationship (QSAR), which is a significant in-silico tool in rational drug design. The QSAR method is used to optimize the existing leads to improve their biological activities, and physicochemical properties and to predict the biological activities of untested and sometimes unavailable compounds, so QSAR is a significant method in drug designing. This article is a comprehensive review of various QSAR studies conducted which help to create new and potent inhibitors for targeting tubulin, a crucial target in cancer treatment. It particularly focuses on studies that provide structural insights into the compounds targeting tubulin. It should prioritize continually researching specific scaffolds, with a focus on important attachment regions, to gather more powerful molecular data and enhance models. This will lead to a better understanding of drug interactions and the development of improved cancer-targeting inhibitors for tubulin.Communicated by Ramaswamy H. Sarma.

LCN2-Fungal siderophore-iron binding and uptake leads to oxidative stress and cell death in hepatocellular carcinoma cell line HepG2.

Microorganisms produce non-ribosomal peptides called siderophores for the purpose of iron acquisition. Mammalian immune system is well-known for producing small secretory proteins called lipocalins upon bacterial infection. These proteins sequester siderophores produced by invading bacterial pathogens rendering them unable to acquire iron from the host. However, this is not their sole function. In addition to transferrin and lactoferrin, lipocalins are also known to transport siderophore-bound iron to the host cells. While binding of bacterial siderophores with human lipocalin is well studied, binding of the fungal counterpart is still not confirmed and fully understood. Apart from pathogen-affected cells, developing cancerous cells also show varying expression level of different proteins including those involved in iron transport. The possibility of exogenous fungal siderophore-mediated iron transport via lipocalin and its receptor in mammalian cells has not yet been explored much. In present investigation we have checked differential expression of human lipocalin, LCN2 in hepatocellular carcinoma cell lines HepG2 as well as its normal counterpart WRL-68 and computationally determined the feasibility of LCN2 binding with fungal siderophore. Further in case of a stable complex being formed, whether this complex has the ability to transport iron through its specific receptor was assessed. Also, we have tried to explore possible mechanism of fungal-siderophore mediated oxidative stress leading to significant cell death in cancerous cells. This study will thus be useful towards finding a new way of treating hepatocellular carcinoma via inducing siderophore-mediated cell death in cancerous cells.Communicated by Ramaswamy H. Sarma.

A Drug Repurposing Approach to Identify Therapeutics by Screening Pathogen Box Exploiting SARS-CoV-2 Main Protease.

Coronavirus disease-19 (COVID-19) is caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2) and is responsible for a higher degree of morbidity and mortality worldwide. There is a smaller number of approved therapeutics available to target the SARS-CoV-2 virus, and the virus is evolving at a fast pace. So, there is a continuous need for new therapeutics to combat COVID-19. The main protease (Mpro ) enzyme of SARS-CoV-2 is essential for replication and transcription of the viral genome, thus could be a potent target for the treatment of COVID-19. In the present study, we performed an in-silico screening analysis of 400 diverse bioactive inhibitors with proven antibacterial and antiviral properties against Mpro drug target. Ten compounds showed a higher binding affinity for Mpro than the reference compound (N3), with desired physicochemical properties. Furthermore, in-depth docking and superimposition revealed that three compounds (MMV1782211, MMV1782220, and MMV1578574) are actively interacting with the catalytic domain of Mpro . In addition, the molecular dynamics simulation study showed a solid and stable interaction of MMV178221-Mpro complex compared to the other two molecules (MMV1782220, and MMV1578574). In line with this observation, MM/PBSA free energy calculation also demonstrated the highest binding free energy of -115.8 kJ/mol for MMV178221-Mpro compound. In conclusion, the present in silico analysis revealed MMV1782211 as a possible and potent molecule to target the Mpro and must be explored in vitro and in vivo to combat the COVID-19.

In silico analysis of comparative affinity of phytosiderophore and bacillibactin for iron uptake by YSL15 and YSL18 receptors of Oryza sativa.

Iron is an important micronutrient for plant growth and development. In the case of Oryza sativa, iron is made available primarily with the help of iron chelators called phytosiderophores i.e. variants of deoxymugineic acid (DMA). They bind with ferric ions and get internalized through Yellow Stripe Like transporters viz. YSL15 and YSL18. However, due to low amount of secretion of phytosiderophores, rice suffers from iron deficiency. Alternatively, siderophores of plant growth promoting rhizobacteria may support iron uptake and make it available to plants via transporting ferric ions possibly through the same transporters. Present study aims to assess comparative binding of DMA and a xenosiderophore (siderophores used by organisms other than the ones producing them) of rhizobacteria i.e. bacillibactin with Fe3+ ion and subsequent transporters of rice. Protein-protein interaction and gene expression analysis predicts uptake of Fe3+ by YSL15 from the rhizosphere region and further distribution through YSL18 with the help of various predicted functional partners. Docking studies confirm the thermodynamically more favourable structure of bacillibactin-Fe3+ complex than DMA-Fe3+ complex. Molecular modelling of YSL15 and YSL18 was done through ab initio method and their evaluation by Ramachandran plot, ProSA, ERRAT value and verify 3 D score revealed a good quality models. Comparative binding assessment through docking and molecular dynamics simulation suggests better binding energies of YSL transporters with bacillibactin-Fe3+ complex as compared to DMA-Fe3+ complex. The current study suggests possible application of xenosiderophores of PGPR origin in supporting plant growth via iron uptake and distribution in rice.Communicated by Ramaswamy H. Sarma.

Linking co-expression modules with phenotypes.

The method for quantifying the association between co-expression module and clinical trait of interest requires application of dimensionality reduction to summaries modules as one dimensional (1D) vector. However, these methods are often linked with information loss. The amount of information lost depends upon the percentage of variance captured by the reduced 1D vector. Therefore, it is of interest to describe a method using analysis of rank (AOR) to assess the association between module and clinical trait of interest. This method works with clinical traits represented as binary class labels and can be adopted for clinical traits measured in continuous scale by dividing samples in two groups around median value. Application of the AOR method on test data for muscle gene expression profiles identifies modules significantly associated with diabetes status.

Designing Self-Inhibitory fusion peptide analogous to viral spike protein against novel severe acute respiratory syndrome (SARS-CoV-2).

COVID-19 is a highly contagious viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is declared pandemic by the World Health Organization (WHO). The spike protein of SARS-CoV-2 is a key component playing a pivotal role in facilitating viral fusion as well as release of genome into the host cell. Till date there is no clinically approved vaccine or drug available against Covid-19. We designed four hydrophobic inhibitory peptides (ITPs) based on WWIHS (Wimley and White interfacial hydrophobicity scale) score, targeting the HR1 domain of spike protein. Two inhibitory peptides out of four have a strong affinity to the hydrophobic surface of HR1 domain in pre-fusion spike protein. The MD simulation result showed the strong accommodation of ITPs with HR1 domain surface. These self-inhibitory peptides mimic the function of HR2 by binding to HR1 domain, thus inhibiting the formation of HR1-HR2 post-fusion complex, which is a key structure for virus-host tropism.Communicated by Ramaswamy H. Sarma.

Deciphering foot-and-mouth disease (FMD) virus-host tropism.

The pattern of interactions between foot and mouth disease (FMD) viral protein 1 (VP1) with susceptible and resistant host integrins were deciphered. The putative effect of site-directed mutation on alteration of interaction is illustrated using predicted and validated 3D structures of VP1, mutated VP1 and integrins of Bos taurus, Gallus and Canis. Strong interactions were observed between FMDV-VP1 protein motifs at conserved tripeptide, Arg-Gly-Asp 143RGD145 and at domain 676SIPLQ680 in alpha-integrin of B. taurus. Notably, in-silico site-directed mutation in FMDV-VP1 protein led to complete loss of interaction between FMD-VP1 protein and B. taurus integrin, which confirmed the active role of arginine-glycine-aspartic acid (RGD) domain. Interestingly, in-vitro analysis demonstrates the persistence of the putative tropism site 'SIPLQ' in different cattle breeds undertaken. Thus, the attempt to decipher the tropism of FMDV at host receptor level interaction might be useful for future FMD control strategies through development of mimetic marker vaccines and/or host receptor manipulations. Communicated by Ramaswamy H. Sarma.