Comprehensive identification, characterization and expression analysis of genes underpinning heat acclimatization in Triticum durum and Aegilops tauschii.

Wheat (Triticum aestivum L.) is an important cereal crop cultivated and consumed worldwide. Global warming-induced escalation of temperature during the seedling and grain-filling phase adversely affects productivity. To survive under elevated temperatures, most crop plants develop natural mechanisms at molecular level by activating heat shock proteins. However, other heat stress-related proteins like heat acclimatization (HA) proteins are documented in hexaploid wheat but have not been explored in detail in its diploid and tetraploid progenitors, which might help to overcome elevated temperature regimes for short periods. Our study aims to explore the potential HA genes in progenitors Triticum durum and Aegilops tauschii that perform well at higher temperatures. Seven genes were identified and phylogenetically classified into three families: K homology (KH), Chloroplast protein-enhancing stress tolerance (CEST), and heat-stress-associated 32 kDa (HSA32). Protein-protein interaction network revealed partner proteins that aid mRNA translation, protein refolding, and reactive species detoxification. Syntenic analysis displayed highly conserved relationships. RT-qPCR-based expression profiling revealed HA genes to exhibit diverse and dynamic patterns under high-temperature regimes, suggesting their critical role in providing tolerance to heat stress. The present study furnishes genetic landscape of HA genes that might help in developing climate-resilient wheat with higher acclimatization potential.

Discovery of fluorinated 2­Styryl 4(3H)-quinazolinone as potential therapeutic hit for oral cancer.

Oral squamous cell carcinoma (OSCC) is the most common malignant epithelial neoplasm, affects the mouth and throat, and accounts for 90 % of oral cancers. Considering the associated morbidity with neck dissections and the limitation of existing therapeutic agents, the discovery and development of new anticancer drugs/drug candidates for oral cancer treatment are of the utmost need. In this context, reported here is the identification of fluorinated 2­styryl 4(3H)-quinazolinone as a promising hit for oral cancer. Preliminary studies indicate that the compound blocks the transition of G1 to S phase, thereby leading to arrest in the G1/S phase. Subsequent RNA-seq analysis revealed that the compound induces the activation of molecular pathways involved in apoptosis (such as TNF signalling through NF-κB, p53 pathways) and cell differentiation and suppresses the pathways of cellular growth and development (such as KRAS signaling) in CAL-27 cancer cells. It is noted that identified hit complies with a favorable range of ADME properties as per the computational analysis.

Self-powered, low-noise and high-speed nanolayered MoSe2/p-GaN heterojunction photodetector from ultraviolet to near-infrared wavelengths.

Integration of nanolayered metal chalcogenides with wide-bandgap semiconductors forming pn heterojunction leads to the way of high-performance photodetection. This work demonstrates the fabrication of a few nanometer thick Molybdenum diselenide (MoSe2)/Mg-doped Gallium Nitride (p-GaN) heterostructure for light detection purposes. The device exhibits low noise broadband spectral response from ultraviolet to near-infrared range (300-950 nm). The band-alignment and the charge transfer at the MoSe2/p-GaN interface promote self-powered photodetection with high photocurrent to dark current ratio of 2000 and 1000 at 365 nm and 640 nm, respectively. A high responsivity of 130 A W-1, detectivity of 4.8 × 1010Jones, and low noise equivalent power of 18 fW/Hz1/2at 365 nm is achieved at an applied bias of 1 V. Moreover, the transient measurements reveal a fast rise/fall time of 407/710µsec for the fabricated device. These outcomes exemplify the viability of MoSe2/p-GaN heterostructure for high-speed and low-noise broadband photodetector applications.

Design, synthesis and in-vitro evaluation of fluorinated triazoles as multi-target directed ligands for Alzheimer disease.

Alzheimer disease is multi-factorial and inflammation plays a major role in the disease progression and severity. Metals and reactive oxygen species (ROS) are the key mediators for inflammatory conditions associated with Alzheimer's. Along multi-factorial nature, major challenge for developing new drug is the ability of the molecule to cross blood brain barrier (BBB). We have designed and synthesized multi-target directed hexafluorocarbinol containing triazoles to inhibit Amyloid ß aggregation and simultaneously chelate the excess metals present in the extracellular space and scavenge the ROS thus reduce the inflammatory condition. From the screened compound library, compound 1c found to be potent and safe. It has demonstrated inhibition of Amyloid ß aggregation (IC50 of 4.6 µM) through selective binding with Amyloid ß at the nucleation site (evidenced from the molecular docking). It also chelate metals (Cu+2, Zn+2 and Fe+3) and scavenges ROS significantly. Due to the presence of hexafluorocarbinol moiety in the molecule it may assist to permeate BBB and improve the pharmacokinetic properties. The in-vitro results of compound 1c indicate the promiscuity for the development of hexafluorocarbinol containing triazoles amide scaffold as multi-target directed therapy against Alzheimer disease.

Discovery of boronic acid-based potent activators of tumor pyruvate kinase M2 and development of gastroretentive nanoformulation for oral dosing.

Several studies have established that cancer cells explicitly over-express the less active isoform of pyruvate kinase M2 (PKM2) is critical for tumorigenesis. The activation of PKM2 towards tetramer formation may increase affinity towards phosphoenolpyruvate (PEP) and avoidance of the Warburg effect. Herein, we describe the design, synthesis, and development of boronic acid-based molecules as activators of PKM2. The designed molecules were inspired by existing anticancer scaffolds and several fragments were assembled in the derivatives. 6a-6d were synthesized using a multi-step synthetic strategy in 55-70% yields, starting from cheap and readily available materials. The compounds were selectively cytotoxic to kill the cancerous cells at 80 nM, while they were non-toxic to the normal cells. The kinetic studies established the compounds as novel activators of PKM2 and (E/Z)-(4-(3-(2-((4-chlorophenyl)amino)-4-(dimethylamino)thiazol-5-yl)-2-(ethoxycarbonyl)-3-oxoprop-1-en-1-yl) phenyl)boronic acid (6c) emerged as the most potent derivative. 6c was further evaluated using various in silico tools to understand the molecular mechanism of tetramer formation. Docking studies revealed that 6c binds to the PKM2 dimer at the dimeric interface. Further to ascertain the binding site and mechanism of action, rigorous MD (molecular dynamics) simulations were undertaken, which led to the conclusion that 6c stabilizes the center of the dimeric interface that possibly promotes tetramer formation. We further planned to make a tablet of the developed molecule for oral delivery, but it was seriously impeded owing to poor aqueous solubility of 6c. To improve aqueous solubility and retain 6c at the lower gastrointestinal tract, thiolated chitosan-based nanoparticles (TCNPs) were prepared and further developed as tablet dosage form to retain anticancer potency in the excised goat colon. Our findings may provide a valuable pharmacological mechanism for understanding metabolic underpinnings that may aid in the clinical development of new anticancer agents targeting PKM2.

Presence of Intra-helical Salt-Bridge in Loop E Half-Helix Can Influence the Transport Properties of AQP1 and GlpF Channels: Molecular Dynamics Simulations of In Silico Mutants.

Major intrinsic protein (MIP) superfamily contains water-transporting AQP1 and glycerol-specific GlpF belonging to two major phylogenetic groups, namely aquaporins (AQPs) and aquaglyceroporins (AQGPs). MIP channels have six transmembrane helices (TM1 to TM6) and two half-helices (LB and LE). LE region contributes two residues to the aromatic/arginine (Ar/R) selectivity filter (SF) within the MIP channel. Bioinformatics analyses have shown that all AQGPs have an intra-helical salt-bridge (IHSB) in LE half-helix and all AQGPs and majority of AQPs have helix destabilizing Gly and/or Pro in the same region. In this paper, we mutated in silico the acidic and basic residues in GlpF to Ser and introduced salt-bridge interaction in AQP1 LE half-helix by substituting Ser residues at the equivalent positions with acidic and basic residues. We investigated the influence of IHSB in LE half-helix on the transport properties of GlpF and AQP1 mutant channels using molecular dynamics simulations. With IHSB abolished in LE half-helix, the GlpF mutant exhibited a significantly reduced water transport. In contrast, the introduction of IHSB in the two AQP1 mutants has increased water transport. Absence of salt-bridge in LE half-helix alters the SF geometry and results in a higher energy barrier for the solutes in the Ar/R selectivity filter. Presence/absence of IHSB in LE half-helix influences the channel transport properties and it is evident especially for the AQGPs. By modulating its helical flexibility, LE half-helix can perhaps play a regulatory role in transport either on its own or in conjunction with other extracellular regions.

EncoderMap(II): Visualizing Important Molecular Motions with Improved Generation of Protein Conformations.

Dimensionality reduction can be used to project high-dimensional molecular data into a simplified, low-dimensional map. One feature of our recently introduced dimensionality reduction technique EncoderMap, which relies on the combination of an autoencoder with multidimensional scaling, is its ability to do the reverse. It is able to generate conformations for any selected points in the low-dimensional map. This transfers the simplified, low-dimensional map back into the high-dimensional conformational space. Although the output is again high-dimensional, certain aspects of the simplification are preserved. The generated conformations only mirror the most dominant conformational differences that determine the positions of conformational states in the low-dimensional map. This allows depicting such differences and-in consequence-visualizing molecular motions and gives a unique perspective on high-dimensional conformational data. In our previous work, protein conformations described in backbone dihedral angle space were used as the input for EncoderMap, and conformations were also generated in this space. For large proteins, however, the generation of conformations is inaccurate with this approach due to the local character of backbone dihedral angles. Here, we present an improved variant of EncoderMap which is able to generate large protein conformations that are accurate in short-range and long-range orders. This is achieved by differentiable reconstruction of Cartesian coordinates from the generated dihedrals, which allows adding a contribution to the cost function that monitors the accuracy of all pairwise distances between the Cα-atoms of the generated conformations. The improved capabilities to generate conformations of large, even multidomain, proteins are demonstrated for two examples: diubiquitin and a part of the Ssa1 Hsp70 yeast chaperone. We show that the improved variant of EncoderMap can nicely visualize motions of protein domains relative to each other but is also able to highlight important conformational changes within the individual domains.

Wound healing effect of ethanolic extract from Morning Glory (Ipomoea carnea Jacq.) leaves by using different models in rats.

Current study aims to evaluate the wound healing effect with apparent mechanism and determination of flavonoid (quercetin) from ethanol extract of Ipomea carnea jacq. leaves, family Convolvulaceae. The wound healing effect of ethanol extract from I. carnea jacq. leaves screened by excision and incision wound methods in rats. Five groups (Negative control, vehicle control, 2.5%w/w, 5% w/w ethanol extract ointment and 5%w/w Reference Ointment Povidone-iodine group) of rats (n-6) were experimentally wounded at dorsal portion of rats. The 5% w/w ointment of ethanol extract found significant wound contraction at 18-20th days, greater tensile strength, and biochemical parameters. Ethyl acetate fraction of ethanolic extract was analysed by RP-HPLC and retention time was found 3.042 min. The percentage of quercetin was found in I. carnea leaves as 0.842%. The results were supported by histopathological studies which showed augment in terms of collagen fibers, fibroblast and new blood vessels. The results were evidently exhibited the traditional uses of I. carnea leaves for wound healing effects. The healing effect may be attributed by presence of flavonoid and other compounds present in the leaves with free radical scavenging mechanism.

A rare case of movement disorder in Intensive Care Unit.

Hemichorea-hemiballismus syndrome (HCHB represents a peculiar form of hyperkinetic movement disorder with varying degrees of chorea and/or ballistic movements on one side of body. The patients are conscious of their environment but unable to control the movements. HCHB is a rare occurrence in acute stroke patients. Patients with sub-cortical strokes are more prone to develop movement disorders than with cortical stroke. We report one such interesting case here posing difficulties in management and intensive care of the patient. The patient remained refractory to all the drugs described in literature, and adequate control of the hyperkinetic movements could be achieved only with continuous intravenous sedation.

A rare case of idiopathic cluster of differentiation 4(+) T-cell lymphocytopenia presenting with disseminated tubercular infection.

Idiopathic cluster of differentiation 4(+) (CD4(+)) T-cell lymphocytopenia is a rare heterogeneous clinical syndrome characterized by low absolute CD4 counts on two different occasions without any evidence of other known cause of immunodeficiency including human immunodeficiency virus (HIV), infections or drugs associated with fall in CD4(+) count. Also referred to as severe unexplained HIV seronegative immune suppression by the World Health Organization, it was first described by Centers for Disease Control in 1992 in patients with opportunistic infections who were negative for HIV but had low CD4 counts. Patients typically present with opportunistic infections, malignancies, or autoimmune disorders. There have been case reports on opportunistic infections such as cryptococcal meningitis or non-Mycobacterium tuberculosis infections in these patients. However, no case of disseminated M. tuberculosis has been reported as such in Indian literature. We present a case of disseminated tuberculosis with low CD4 counts without any evidence of HIV infection.

Oxygen-aromatic contacts in intra-strand base pairs: analysis of high-resolution DNA crystal structures and quantum chemical calculations.

Three-dimensional structures of biomolecules are stabilized by a large number of non-covalent interactions and some of them such as van der Waals, electrostatic and hydrogen bond interactions are well characterized. Delocalized π-electron clouds of aromatic residues are known to be involved in cation-π, CH-π, OH-π and π-π interactions. In proteins, many examples have been found in which the backbone carbonyl oxygen of one residue makes close contact with the aromatic center of aromatic residues. Quantum chemical calculations suggest that such contacts may provide stability to the protein secondary structures. In this study, we have systematically analyzed the experimentally determined high-resolution DNA crystal structures and identified 91 examples in which the aromatic center of one base is in close contact (<3.5Ǻ) with the oxygen atom of preceding (Group-I) or succeeding base (Group-II). Examples from Group-I are overwhelmingly observed and cytosine or thymine is the preferred base contributing oxygen atom in Group-I base pairs. A similar analysis of high-resolution RNA structures surprisingly did not yield many examples of oxygen-aromatic contact of similar type between bases. Ab initio quantum chemical calculations on compounds based on DNA crystal structures and model compounds show that interactions between the bases in base pairs with oxygen-aromatic contacts are energetically favorable. Decomposition of interaction energies indicates that dispersion forces are the major cause for energetically stable interaction in these base pairs. We speculate that oxygen-aromatic contacts in intra-strand base pairs in a DNA structure may have biological significance.

Molecular dynamics simulations of peptides at the air-water interface: influencing factors on peptide-templated mineralization.

Biomineralization is the intricate, biomedically highly relevant process by which living organisms deposit minerals on biological matrices to stiffen tissues and build skeletal structures and shells. Rapaport and coworkers ( J. Am. Chem. Soc. 2000 , 122 , 12523 ; Adv. Funct. Mater. 2008 , 18 , 2889 ; Acta Biomater. 2012 , 8 , 2466 ) have designed a class of self-assembling amphiphilic peptides that are capable of forming hydrogels and attracting ions from the environment, generating structures akin to the extracellular matrix and promoting bone regeneration. The air-water interface serves both in experiment and in simulations as a model hydrophobic surface to mimic the cell's organic-aqueous interface and to investigate the organization of the peptide matrix into ordered ß-pleated monolayers and the subsequent onset of biomineral formation. To obtain insight into the underlying molecular mechanism, we have used molecular dynamics simulations to study the effect of peptide sequence on aggregate stability and ion-peptide interactions. We find-in excellent agreement with experimental observations-that the nature of the peptide termini (proline vs phenylalanine) affect the aggregate order, while the nature of the acidic side chains (aspartic vs glutamic acid) affect the aggregate's stability in the presence of ions. These simulations provide valuable microscopic insight into the way ions and peptide templates mutually affect each other during the early stages of biomineralization preceding nucleation.

Deciphering the complex landscape of post-translational modifications on PKM2: Implications in head and neck cancer pathogenesis.

In the vast landscape of human health, head and neck cancer (HNC) poses a significant health burden globally, necessitating the exploration of novel diagnostics and therapeutics. Metabolic alterations occurring within tumor microenvironment are crucial to understand the foundational cause of HNC. Post-translational modifications (PTMs) have recently emerged as a silent foe exerting a significantly heightened influence on various aspects of the biological processes associated with the onset and advancement of cancer, particularly in the context of HNC. There are numerous targets involved in HNC but recently, the enzyme pyruvate kinase M2 (PKM2) has come out as a hot target due to its involvement in glycolysis resulting in metabolic reprogramming of cancer cells. Various PTMs have been reported to affect the structure and function of PKM2 by modulating its activity. This review aims to investigate the impact of PTMs on the interaction between PKM2 and several signaling pathways and transcription factors in the context of HNC. These interactions possess significant ramification for cellular proliferation, apoptosis, angiogenesis and metastasis. This review primarily explores the role of PTMs influencing PKM2 and its involvement in tumor development. While acknowledging the significance of PKM2 interactions with other tumor regulators, the emphasis lies on dissecting PTM-related mechanisms rather than solely scrutinizing individual regulators. It lays the framework for the development of more sophisticated diagnostic tools and uncovers exciting possibilities for precision medicine essential for effectively addressing the complexity of this malignancy in a precise and focused manner.

Amyloid Mimicking Assemblies Formed by Glutamine, Glutamic Acid, and Aspartic Acid.

The aggregation of amino acids into amyloid-like structures is a critical phenomenon for understanding the pathophysiology of various diseases, including inborn errors of metabolism (IEMs) associated with amino acid imbalances. Previous studies have primarily focused on self-assembly of aromatic amino acids, leading to a limited understanding of nonaromatic, polar amino acids in this context. To bridge this gap, our study investigates the self-assembly and aggregation behavior of specific nonaromatic charged and uncharged polar amino acids l-glutamine (Gln), l-aspartic acid (Asp), and l-glutamic acid (Glu), which have not been reported widely in the context of amyloid aggregation. Upon aging these amino acids under controlled conditions, we observed the formation of uniform, distinct aggregates, with Gln forming fibrillar gel-like structures and Glu exhibiting fibrous globular morphologies. Computational simulations validated these findings, identifying Gln as the most potent in forming stable aggregates, followed by Glu and Asp. These simulations elucidated the driving forces behind the distinct morphologies and stabilities of the aggregates. Thioflavin T assays were employed to confirm the amyloid-like nature of these aggregates, suggesting their potential cytotoxic impact. To assess toxicity, we performed in vitro studies on neural cell lines and in vivo experiments in Caenorhabditis elegans (C. elegans), which demonstrated measurable cytotoxic effects, corroborated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and heat shock survival assays. Importantly, this study fills a critical gap in our understanding on the role of nonaromatic amino acids in amyloidogenesis and its implications for IEMs. Our findings provide a foundation for future investigations into the mechanisms of diseases associated with amino acid accumulation and offer potential avenues for the development of targeted therapeutic strategies.

In-silico and in-vitro hybrid approach to identify glucagon-like peptide-1 receptor agonists from anti-diabetic natural products.

Natural products have contributed immensely towards the treatment of various diseases including diabetes. Here, a database of small molecules from nature possessing antidiabetic properties was analysed and shortlisted according to their structural diversity. Later, those structures were screened by in-silico docking studies to understand their affinity towards glucagon-like peptide-1 (GLP-1) receptor. The selected molecules were isolated and investigated further by integrated in-vitro and in-silico approaches. Alpha-mangostin was found to be suitable due to its excellent docking score and isolation yield. A pancreatic beta cell line was used to test the activity of alpha-mangostin and observed a 3-fold increase in insulin secretion compared to 15 mM glucose control. Further, in-silico molecular dynamics simulations studies have validated its target by showing conformational changes at the functionally active part of the GLP-1 receptor. This screening strategy can be applied to identify pertinent natural products rapidly for various therapeutic targets.

Fabrication of polypyrrole gas sensor for detection of NH3 using an oxidizing agent and pyrrole combinations: Studies and characterizations.

The organic polymer known as Polypyrrole (Ppy) is synthesized when pyrrole monomers are polymerized. Excellent thermal stability, superior electrical conductivity, and environmental stability are all characteristics of Polypyrrole. Chemical oxidative polymerization was used to synthesize Ppy using Ferric chloride (FeCl3) as an oxidizing agent and surfactant CTAB in aqueous solution. Oxidant (FeCl3) to pyrrole varied in different molar ratios (2, 3, 4 and 5). It was found that increasing this ratio up to 4 increases PPy's conductivity. XRD, FTIR, and SEM were used to characterize Ppy. The conductive nature of Ppy was studied by I-V characteristics. The best conductive polymer is studied for the NH3 gas response.

Targeting multidrug resistant Staphylococcus aureus with cationic chlorpromazine-peptide conjugates.

Antimicrobial resistance is a serious public health risk. Its severity is fueled on an unprecedented scale, necessitating the demand for novel antimicrobial scaffolds aimed at novel targets. Herein, we present cationic chlorpromazine peptide conjugates that are rationally intended to targetmultidrug-resistant (MDR) bacteria. The most potent compound, CPWL, of all the conjugates evaluated, showed promising antibacterial activity against clinical, MDR S. aureus, with no cytotoxicity. The molecular docking experiments confirmed that CPWL possessed a very high affinity for S. aureus enoyl reductase (saFabI). Furthermore, CPWL antibacterial action against saFabI was further corroborated by MD simulation studies. Thus, our findings highlight cationic chlorpromazine as a promising scaffold for the development of saFabI inhibitors to target severe staphylococcal infections.

Structural basis of Omicron immune evasion: A comparative computational study.

BACKGROUND: The vaccines used against SARS-CoV-2 by now have been able to develop some neutralising antibodies in the vaccinated population and their effectiveness has been challenged by the emergence of the new strains with numerous mutations in the spike protein of SARS-CoV-2. Since S protein is the major immunogenic protein of the virus which contains Receptor Binding Domain (RBD) that interacts with the human Angiotensin-Converting Enzyme 2 (ACE2) receptors, any mutations in this region should affect the neutralisation potential of the antibodies leading to the immune evasion. Several variants of concern of the virus have emerged so far, amongst which the most critical are Delta and recently reported Omicron. In this study, we have mapped and reported mutations on the modelled RBD and evaluated binding affinities of various human antibodies with it. METHOD: Docking and molecular dynamics simulation studies have been used to explore the effect of mutations on the structure of RBD and RBD-antibody interaction. RESULTS: These analyses show that the mutations mostly at the interface of a nearby region lower the binding affinity of the antibody by ten to forty percent, with a downfall in the number of interactions formed as a whole. It implies the generation of immune escape variants. CONCLUSIONS: Notable mutations and their effect was characterised that explain the structural basis of antibody efficacy in Delta and a compromised neutralisation effect for the Omicron variant. Thus, our results pave the way for robust vaccine design that can be effective for many variants.

In silico design of multi-epitope-based peptide vaccine against SARS-CoV-2 using its spike protein.

SARS-CoV-2 has been efficient in ensuring that many countries are brought to a standstill. With repercussions ranging from rampant mortality, fear, paranoia, and economic recession, the virus has brought together countries to look at possible therapeutic countermeasures. With prophylactic interventions possibly months away from being particularly effective, a slew of measures and possibilities concerning the design of vaccines are being worked upon. We attempted a structure-based approach utilizing a combination of epitope prediction servers and Molecular dynamic (MD) simulations to develop a multi-epitope-based subunit vaccine that involves the two subunits of the spike glycoprotein of SARS-CoV-2 (S1 and S2) coupled with a substantially effective chimeric adjuvant to create stable vaccine constructs. The designed constructs were evaluated based on their docking with Toll-Like Receptor (TLR) 4. Our findings provide an epitope-based peptide fragment that can be a potential candidate for the development of a vaccine against SARS-CoV-2. Recent experimental studies based on determining immunodominant regions across the spike glycoprotein of SARS-CoV-2 indicate the presence of the predicted epitopes included in this study.Communicated by Ramaswamy H. Sarma.

Knowledge-driven design and optimization of potent symmetric anticancer molecules: A case study on PKM2 activators.

BACKGROUND: Pyruvate kinase M2 (PKM2) is preferentially expressed as a low-activity dimer over the active tetramer in proliferating tumor cells, resulting in metabolic reprogramming to achieve high energy requirements and nutrient uptake. This leads to a shift from the normal glycolytic pathway causing tumor cells to proliferate uncontrollably. This study utilizes knowledge-based drug discovery to determine the critical features from experimentally known PKM2 activators and design compounds that would significantly confer a stable structural and functional edge over the known compounds which are still at the preclinical stage. METHODS: Conscientious molecular modeling studies were carried out and critical structural features were identified and validated from the knowledge of experimentally known PKM2 activators to confer high-binding affinities. A virtual library of 200 palindromic and non-palindromic activators was designed based on these identified critical features to target a distinct activator binding-site. This binding would favor specific dimer-dimer association and subsequent protein tetramerization. The resultant compounds strongly correlated with identified structural features and binding affinities which further strengthened our findings. The designed activators were then subjected to pharmacokinetic profiling and toxicity prediction, followed by free-binding energy calculations and MD simulations. RESULTS: All the virtually designed activators comprising the identified critical features were observed to confer high-binding affinities ranging from -9.1 to -15.0 kcal/mol to the receptor protein. The designed activators also demonstrated optimum pharmacokinetic and toxicity profiles. CONCLUSION: The best activators selected for MD simulations studies were conclusively observed to stabilize the required tetrameric conformation suggesting that these activators could potentially target PKM2 tetramerization that might restore the normal glycolytic pathway and suppress tumor progression.