Biology subjects

Roy, A.

Publications and source records attributed to Roy, A..

At least 109 records · Page 6Linked to original sources

bioRxiv2023

Archaeal origin translation proofreader imparts multialdehyde stress tolerance to land plants

Aldehydes, being an integral part of carbon metabolism, energy generation and signalling pathways, are ingrained in plant physiology. Land plants have developed intricate metabolic pathways which involve production of reactive aldehydes and its detoxification to survive harsh terrestrial environments. Here, we show that physiologically produced aldehydes i.e., formaldehyde and methylglyoxal in addition to acetaldehyde, generate adducts with aminoacyl-tRNAs, a substrate for protein synthesis. Plants are unique in possessing two distinct chiral proofreading systems, D-aminoacyl-tRNA deacylase1 (DTD1) and DTD2, of bacterial and archaeal origins, respectively. Extensive biochemical analysis revealed that only archaeal DTD2 can remove the stable D-aminoacyl adducts on tRNA thereby shielding archaea and plants from these system-generated aldehydes. Using Arabidopsis as a model system, we have shown that the loss of DTD2 gene renders plants susceptible to these toxic aldehydes as they generate stable alkyl modification on D-aminoacyl-tRNAs, which are recycled only by DTD2. Bioinformatic analysis identifies the expansion of aldehyde metabolising repertoire in land plant ancestors which strongly correlates with the recruitment of archaeal DTD2. Finally, we demonstrate that the overexpression of DTD2 offers better protection against aldehydes than in wild-type Arabidopsis highlighting its role as a multi-aldehyde detoxifier that can be explored as a transgenic crop development strategy.

plant biology↗

bioRxiv2023

The IRE1α/XBP1/Myomaker axis drives myoblast fusion in adult skeletal muscle

Skeletal muscle regeneration involves a signaling network that regulates the proliferation, differentiation, and fusion of muscle precursor cells to injured myofibers. Inositol requiring enzyme 1 alpha (IRE1) is one of the arms of the unfolded protein response (UPR) that regulates cellular proteostasis in response to ER stress. Here, we demonstrate that inducible deletion of IRE1 in adult muscle stem cells (i.e. satellite cells) of mice impairs skeletal muscle regeneration primarily through inhibiting myoblast fusion step. Knockdown of IRE1 or its downstream target, X-box protein 1 (XBP1), also inhibits fusion of cultured myoblasts during myogenesis. Genome-wide transcriptome analysis revealed that knockdown of IRE1 or XBP1 deregulates the gene expression of molecules involved in the regulation of myoblast fusion. The IRE1-XBP1 axis mediates the gene expression of multiple profusion molecules, including Myomaker (Mymk) during myogenic differentiation. Our study demonstrates that spliced XBP1 (sXBP1) transcription factor binds to the promoter region of Mymk gene during myogenesis. Overexpression of myomaker in IRE1-knockdown cultures rescues fusion defects. Finally, our results show that inducible deletion of IRE1 in satellite cells inhibits myoblast fusion and myofiber hypertrophy in response to functional overload. Collectively, our study demonstrates that IRE1 promotes myoblast fusion through sXBP1-mediated up-regulation in the gene expression of profusion molecules. Significance StatementMyoblast fusion is an essential step for regeneration and post-natal growth of skeletal muscle. We demonstrate that the activation of the IRE1/XBP1 arm of the unfolded protein response induces myoblast fusion through augmenting the gene expression of multiple profusion molecules, including myomaker. This study has identified a novel signaling axis that link ER stress-induced non-myogenic signaling pathway to myoblast fusion. Augmenting the activity of IRE1/XBP1 pathway could be a potential therapeutic strategy for various muscle degenerative diseases.

cell biology↗

bioRxiv2023

Generating Novel Leads for Drug Discovery using LLMs with Logical Feedback

Large Language Models (LLMs) can be used as repositories of biological and chemical information to generate pharmacological lead compounds. However, for LLMs to focus on specific drug targets typically require experimentation with progressively more refined prompts. Results thus become dependent not just on what is known about the target, but also on what is known about the prompt-engineering. In this paper, we separate the prompt into domain-constraints that can be written in a standard logical form, and a simple text-based query. We investigate whether LLMs can be guided, not by refining prompts manually, but by refining the the logical component automatically, keeping the query unchanged. We describe an iterative procedure LMLF ("Language Models with Logical Feedback") in which the constraints are progressively refined using a logical notion of generalisation. On any iteration, newly generated instances are verified against the constraint, providing "logical-feedback" for the next iterations refinement of the constraints. We evaluate LMLF using two well-known targets (inhibition of the Janus Kinase 2; and Dopamine Receptor D2); and two different LLMs (GPT-3 and PaLM). We show that LMLF, starting with the same logical constraints and query text, can guide both LLMs to generate potential leads. We find: (a) Binding affinities of LMLF-generated molecules are skewed towards higher binding affinities than those from existing baselines; LMLF results in generating molecules that are skewed towards higher binding affinities than without logical feedback; (c) Assessment by a computational chemist suggests that LMLF generated compounds may be novel inhibitors. These findings suggest that LLMs with logical feedback may provide a mechanism for generating new leads without requiring the domain-specialist to acquire sophisticated skills in prompt-engineering.

bioinformatics↗

bioRxiv2023

Transcriptomic response in pyroxsulam-resistant and susceptible Bromus sterilis identified three distinct mechanisms of resistance

Bromus sterilis has evolved into a more predominant weed in the Czech Republics winter wheat fields, owing largely to the widespread application of pyroxsulam for its management. In this study, we report a biotype that has developed resistance to pyroxsulam and has also shown cross- resistance to other herbicides. Although no differences in ploidy levels or no mutations of acetolactate synthase (ALS) were detected, a significant elevation of ALS enzyme activity was observed in the R biotype. Through combined analysis of enzyme inhibition and total transcript expression (RNA-Seq), we have identified differentially expressed transcripts that potentially contribute to pyroxsulam metabolism. Furthermore, we observed a significant increase in the expression of genes involved in redox mechanisms and transporters that could contribute to enhanced resistance to pyroxulam in the R biotype. Our results present a novel understanding of herbicide resistance in B. sterilis through three distinct resistance mechanisms (ALS gene overexpression, enhanced metabolism and reduced translocation) without mutation in the herbicide target protein. This understanding is the foundation for improving management strategies for herbicide resistant B. sterilis.

plant biology↗

bioRxiv2023

Bruno 1 regulates cytoskeleton dynamics and a temporal splicing transition to promote myofibril assembly, growth and maturation in Drosophila flight muscle

Muscles undergo developmental transitions in gene expression and alternative splicing that are necessary to refine sarcomere structure and contractility. CUG-BP and ETR-3-like (CELF) family RNA binding proteins are important regulators of RNA processing during myogenesis that are misregulated in diseases such as myotonic dystrophy (DM1). Here we report a conserved function for Bruno 1 (Bru1, Arrest), a CELF1/2 family homolog in Drosophila, during early muscle myogenesis. Loss of Bru1 in flight muscles results in disorganization of the actin cytoskeleton leading to aberrant myofiber compaction and defects in pre-myofibril formation. Temporally-restricted rescue and RNAi knockdown demonstrate that early cytoskeletal defects interfere with subsequent steps in sarcomere growth and maturation. Early defects are distinct from a later requirement for bru1 to regulate sarcomere assembly dynamics during myofiber maturation. We identify an imbalance in growth in sarcomere length and width during later stages of development as the mechanism driving abnormal radial growth, myofibril fusion and the formation of hollow myofibrils in bru1 mutant muscle. Molecularly, we characterize a genome-wide transition from immature to mature sarcomere gene isoform expression in flight muscle development that is blocked in bru1 mutants. We further demonstrate that temporally restricted Bru1 rescue can partially alleviate hypercontraction in late pupal and adult stages, but it cannot restore myofiber function or correct structural deficits. Our results reveal the conserved nature of CELF function in regulating cytoskeletal dynamics in muscle development, and demonstrate that defective RNA processing due to misexpression of CELF proteins causes wide-reaching structural defects and progressive malfunction of affected muscles that cannot be rescued by late-stage gene replacement.

developmental biology↗

bioRxiv2023

De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8

The RGD (Arg-Gly-Asp)-binding integrins v{beta}6 and v{beta}8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between the two closely related integrin proteins and other RGD integrins, stabilize specific conformational states, and have sufficient stability enabling tissue restricted administration could have considerable therapeutic utility. Existing small molecules and antibody inhibitors do not have all of these properties, and hence there is a need for new approaches. Here we describe a method for computationally designing hyperstable RGD-containing miniproteins that are highly selective for a single RGD integrin heterodimer and conformational state, and use this strategy to design inhibitors of v{beta}6 and v{beta}8 with high selectivity. The v{beta}6 and v{beta}8 inhibitors have picomolar affinities for their targets, and >1000-fold selectivity over other RGD integrins. CryoEM structures are within 0.6-0.7[A] root-mean-square deviation (RMSD) to the computational design models; the designed v{beta}6 inhibitor and native ligand stabilize the open conformation in contrast to the therapeutic anti-v{beta}6 antibody BG00011 that stabilizes the bent-closed conformation and caused on-target toxicity in patients with lung fibrosis, and the v{beta}8 inhibitor maintains the constitutively fixed extended-closed v{beta}8 conformation. In a mouse model of bleomycin-induced lung fibrosis, the v{beta}6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics when delivered via oropharyngeal administration mimicking inhalation, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.

biochemistry↗

bioRxiv2023

Molecular mechanisms of inorganic-phosphate release from the core and barbed end of actin filaments

The release of inorganic phosphate (Pi) from actin filaments constitutes a key step in their regulated turnover, which is fundamental to many cellular functions. However, the molecular mechanisms underlying Pi release from both the core and barbed end of actin filaments remain unclear. Here, we combine cryo-EM with molecular dynamics simulations and in vitro reconstitution to demonstrate how actin releases Pi through a molecular backdoor. While constantly open at the barbed end, the backdoor is predominantly closed in filament-core subunits and only opens transiently through concerted backbone movements and rotameric rearrangements of residues close to the nucleotide binding pocket. This mechanism explains why Pi escapes rapidly from the filament end and yet slowly from internal actin subunits. In an actin variant associated with nemaline myopathy, the backdoor is predominantly open in filament-core subunits, resulting in greatly accelerated Pi release after polymerization and filaments with drastically shortened ADP-Pi caps. This demonstrates that the Pi release rate from F-actin is controlled by steric hindrance through the backdoor rather than by the disruption of the ionic bond between Pi and Mg2+ at the nucleotide-binding site. Our results provide the molecular basis for Pi release from actin and exemplify how a single, disease-linked point mutation distorts the nucleotide state distribution and atomic structure of the actin filament.

biochemistry↗

bioRxiv2023

Uneven terrain versus dual-task walking: differential challenges imposed on walking behavior in older adults are predicted by cognitive and sensorimotor function

Aging is associated with declines in walking function. To understand these mobility declines, many studies have obtained measurements while participants walk on flat surfaces in laboratory settings during concurrent cognitive task performance (dual-tasking). This may not adequately capture the real-world challenges of walking at home and around the community. Here, we hypothesized that uneven terrains in the walking path impose differential changes to walking speed compared to dual-task walking. We also hypothesized that changes in walking speed resulting from uneven terrains will be better predicted by sensorimotor function than cognitive function. Sixty-three community-dwelling older adults (65-93 yrs old) performed overground walking under varying walking conditions. Older adults were classified into two mobility function groups based on scores of the Short Physical Performance Battery. They performed uneven terrain walking across four surface conditions (Flat, Low, Medium, and High unevenness) and performed single and verbal dual-task walking on flat ground. Participants also underwent a battery of cognitive (cognitive flexibility, working memory, inhibition) and sensorimotor testing (grip strength, 2-pt discrimination, pressure pain threshold). Our results showed that walking speed decreased during both dual-task walking and across uneven terrain walking conditions compared to walking on flat terrain. Participants with lower mobility function had even greater decreases in uneven terrain walking speeds. The change in uneven terrain speed was associated with attention and inhibitory function. Changes in both dual-task and uneven terrain walking speeds were associated with 2-point tactile discrimination. This study further documents associations between mobility, executive functions, and somatosensation, highlights the differential costs to walking imposed by uneven terrains, and identifies that older adults with lower mobility function are more likely to experience these changes to walking function.

neuroscience↗

bioRxiv2023

Title: Leveraging Base Pair Mammalian Constraint to Understand Genetic Variation and Human Disease

Although thousands of genomic regions have been associated with heritable human diseases, attempts to elucidate biological mechanisms are impeded by a general inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function that is agnostic to cell type or disease mechanism. Here, single base phyloP scores from the whole genome alignment of 240 placental mammals identified 3.5% of the human genome as significantly constrained, and likely functional. We compared these scores to large-scale genome annotation, genome-wide association studies (GWAS), copy number variation, clinical genetics findings, and cancer data sets. Evolutionarily constrained positions are enriched for variants explaining common disease heritability (more than any other functional annotation). Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.

genomics↗

bioRxiv2022

Effects of microRNA-mediated negative feedback on gene expression noise

Micro-RNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally in eukaryotes by binding with target mRNAs and preventing translation. miRNA-mediated feedback motifs are ubiquitous in various genetic networks which control cellular decision-making. A key question is how such a feedback mechanism may affect gene expression noise. To answer this, we have developed a mathematical model to study the effects of a miRNA-dependent negative feedback loop on mean expression and noise in target mRNAs. Combining analytics and simulations, we show the existence of an expression threshold demarcating repressed and expressed regimes in agreement with earlier studies. The steady-state mRNA distributions are bimodal near the threshold, where copy numbers of mRNAs and miRNAs exhibit enhanced anticorrelated fluctuations. Moreover, variation of negative-feedback strength shifts the threshold locations and modulates the noise profiles. Notably, the miRNA-mRNA binding affinity and feedback strength collectively shape the bimodality. We also compare our model with a direct auto-repression motif, where a gene produces its own repressor. Auto-repression fails to produce bimodal mRNA distributions as found in miRNA-based indirect repression, suggesting the crucial role of miRNAs in creating phenotypic diversity. Together, we demonstrate how miRNA-dependent negative feedback modifies the expression threshold and leads to a broader parameter regime of bimodality compared to the no-feedback case.

biophysics↗

bioRxiv2022

The Arabidopsis ARID-HMG protein AtHMGB15 modulates JA signalling by regulating MYC2 during pollen development

In flowering plants, jasmonic acid (JA) signalling regulates the complex process of male gametophyte development. JA signalling initiates with the activation of MYC2 transcription factor, for the expression of several JA responsive genes throughout stamen development and pollen maturation. However, the regulation of JA signalling during different developmental stages of male gametophytes is still less understood. In this study we have characterized T-DNA insertion line of AtHMGB15. Phenotypic characterization of athmgb15-4 mutant plants showed delayed bolting, shorter siliques and reduced seed set compared to wildtype. Moreover, deletion of AtHMGB15 resulted in defective pollen morphology, delayed pollen germination, abberant pollen tube growth and a higher percentage of non-viable pollen population in athmgb15-4 compared to wildtype. Molecular analysis indicated down-regulation of JA-biosynthesis and JA-signalling genes viz MYC2, MYB21 and MYB24 in athmgb15-4 mutant. Furthermore, jasmonic acid and its derivatives were found almost ten-fold lower in athmgb15-4 flowers. However, exogenous application of jasmonate could restore pollen morphology and pollen germination, suggesting that impaired JA signalling is responsible for the pollen phenotype in athmgb15 mutant. AtHMGB15 physically interacts with MYC2 protein to form the transcription activation complex for promoting transcription of genes responsible for JA signalling during stamen and pollen development. Collectively, our findings indicate that AtHMGB15, a plant specific DNA binding protein of the ARID-HMG group, acts as a positive regulator of JA signalling to control the spatiotemporal expression of key regulators responsible for stamen and pollen development.

developmental biology↗

bioRxiv2022

Using evolutionary constraint to define novel candidate driver genes in medulloblastoma

Current knowledge of cancer genomics is biased against non-coding mutations. Here, we use whole genome sequencing data from pediatric brain tumors, combined with evolutionary constraint inferred from 240 mammals to identify genes enriched in non-coding constraint mutations (NCCMs). We compare medulloblastoma (MB, malignant) to pilocytic astrocytoma (PA, benign) and find drastically different NCCM frequencies between the two. In PA, a high NCCM frequency only affects the BRAF locus, while in MB, >500 genes have high levels of NCCMs. Intriguingly, many genes are associated with different age of onset, such as HOXB1 in young patients and NUAK1 in adult patients. Our analysis points to different molecular pathways in different patient groups. These novel candidate driver genes may assist patient stratification in MB and may be useful for treatment options. One-Sentence SummaryNon-coding constraint mutations implicate novel candidate genes to stratify medulloblastoma by age and subgroups.

cancer biology↗

bioRxiv2022

Molecular fingerprints are not useful in large-scale search for similarly active compounds

Computational approaches for small-molecule drug discovery now regularly scale to consideration of libraries containing billions of candidate small molecules. One promising approach to increased speed in evaluating billion-molecule libraries is to develop succinct representations of each molecule that enable rapid identification of molecules with similar properties. Molecular fingerprints are thought to provide a mechanism for producing such representations. Here, we explore the utility of commonly-used fingerprints in the context of predicting similar molecular activity. We show that fingerprint similarity provides little discriminative power between active and inactive molecules for a target protein based on a known active - while they may sometimes provide some enrichment for active molecules in a drug screen, a screened dataset will still be dominated by inactive molecules. We also demonstrate that high-similarity actives appear to share a scaffold with the query active, meaning that they could more easily be identified by structural enumeration. Furthermore, even when limited to only active molecules, fingerprint similarity values do not correlate with compound potency. In sum, these results highlight the need for a new wave of molecular representations that will improve the capacity to detect biologically active molecules based on similarity to other such molecules.

pharmacology and toxicology↗

bioRxiv2022

Transcription factor TFII-I fine tunes innate properties of B lymphocytes

The ubiquitously expressed transcription factor TFII-I is a multifunctional protein with pleiotropic roles in gene regulation. TFII-I associated polymorphisms are implicated in Sjogrens syndrome and Lupus in humans and, germline deletion of the Gtf2i gene in mice leads to embryonic lethality. Here we report a unique role for TFII-I in homeostasis of innate properties of B lymphocytes. Loss of Gtf2i in murine B lineage cells leads to a change in transcriptome and chromatin landscape, which resembles myeloid-like features and coincides with enhanced sensitivity to LPS induced transcription. TFII-I deficient B cells also show increased switching to IgG3, a phenotype associated with inflammation. These results demonstrate a role for TFII-I in maintaining immune homeostasis and provide clues for GTF2I polymorphisms associated with B cell dominated autoimmune diseases in humans.

immunology↗

bioRxiv2022

Effect of 15 days hindlimb unloading on baroreflex sensitivity, Hear rate variability and Carotid artery structure in rats

IntroductionIn space, cephalad shift of body fluid equalizes the blood pressure throughout the body leading to various cardiovascular disturbances in space and upon return on earth. Effects of microgravity on humans can be simulated on earth by hindlimb unloading (HU) rat models l. This study was planned to examine the Effect of 15 days hindlimb unloading on baroreflex sensitivity, Herat rate variability (HRV) and carotid artery structure in rats. Material and methods18 male Wistar rats weighing 250-300 gm were randomly divided into control and hindlimb unloading groups and housed in separate cages for 15 days. Body weight, food and water intake was measured every day. The pelvic suspension method was used to simulate effects of microgravity. To record HRV, ECG was recorded in lead II configuration on the 15th day. Then blood pressure was recorded directly from the carotid artery. Linear regression of arterial pressure and RR interval used to derive the Baroreflex sensitivity. Vessel wall thickness, intimal thickness, smooth muscle cell layer thickness & luminal diameter were compared after H&E staining. Ultrathin sectioning and counter-staining was done for electron microscopy and Changes in endothelial thickness, elastic lamina, and deeper artery structures were observed. Statistical analysis was done using Graphpad Prism (version 9.0). Unpaired t-test, Mann Whitney and 2 way ANOVA were used according to groups and distribution of parameters. ResultsWe found significant differences in Food intake (p {square}0.001), Body weight (p {square}0.001), Heart rate (p=0.031), BRS (p= 0.026), R-R interval (p=0.0246), heart rate variability parameters {SDSD (p=0.0001), RMSD (p= 0.0001), VLF(p=0.001),HF (p=0.0054), LF/HF Ratio (p= 0.0001)}. We did not found significant changes in Water intake, MAP, SBP, DBP, Vessel wall thickness, Luminal Diameter, Intimal thickness, Smooth muscle thickness, in H&E staining and in electron microscopy. ConclusionChronic microgravity simulation using pelvic suspension showed a decrease in BRS after 15 days of HU; however 15 days of HU was not insufficient to produce any structural changes in the carotid artery. BRS changes were accompanied by change in vascular vasoconstriction and vasodilation properties which were due to alteration in the sympathetic and parasympathetic outflow.

physiology↗

bioRxiv2022

Combining phenotypic and genomic data to improve prediction of binary traits

Plant breeders want to develop cultivars that outperform existing genotypes. Some characteristics (here main traits) of these cultivars are categorical and difficult to measure directly. It is important to predict the main trait of newly developed genotypes accurately. In addition to marker data, breeding programs often have information on secondary traits (or phenotypes) that are easy to measure. Our goal is to improve prediction of main traits with interpretable relations by combining the two data types using variable selection techniques. However, the genomic characteristics can overwhelm the set of secondary traits, so a standard technique may fail to select any phenotypic variables. We develop a new statistical technique that ensures appropriate representation from both the secondary traits and the phenotypic variables for optimal prediction. When two data types (markers and secondary traits) are available, we achieve improved prediction of a binary trait by two steps that are designed to ensure that a significant intrinsic effect of a phenotype is incorporated in the relation before accounting for extra effects of genotypes. First, we sparsely regress the secondary traits on the markers and replace the secondary traits by their residuals to obtain the effects of phenotypic variables as adjusted by the genotypic variables. Then, we develop a sparse logistic classifier using the markers and residuals so that the adjusted phenotypes may be selected first to avoid being overwhelmed by the genotypes due to their numerical advantage. This classifier uses forward selection aided by a penalty term and can be computed effectively by a technique called the one-pass method. It compares favorably with other classifiers on simulated and real data.

genomics↗

bioRxiv2022

Temporal regulation of TAK1 to counteract muscular dystrophy

Muscular dystrophy is a group of genetic neuromuscular disorders that involves severe muscle wasting. Transforming growth factor {beta}-activated kinase 1 (TAK1) is an important signaling protein that regulates cell survival, growth, and inflammation. TAK1 has been recently found to promote myofiber growth in skeletal muscle of adult mice. However, the role of TAK1 in muscle disorders remains poorly understood. In the present study, we have investigated how TAK1 affects progression of dystrophic phenotype in the mdx mouse model of Duchnne muscular dystrophy (DMD). TAK1 is highly activated during peak necrotic phase in mdx mice. Targeted inducible inactivation of TAK1 inhibits muscle injury, necroptosis, and accumulation of macrophages in dystrophic muscle of mdx mice. Additionally, targeted inactivation of TAK1 leads to the activation of autophagy and Notch and Wnt signaling in the dystrophic muscle. However, inactivation of TAK1 significantly reduces myofiber size and muscle contractile function in both young and adult mdx mice. Forced activation of TAK1 in skeletal muscle after peak necrotic phase induces myofiber growth and improves muscle histopathology in mdx mice. Our results suggest that targeted activation of TAK1 can ameliorate disease progression and improve muscle growth in DMD. One Sentence SummaryOur results demonstrate that duly regulation of TAK1 activity ameliorates dystrophic phenotype in a mouse model of Duchnne Muscular Dystrophy.

physiology↗

bioRxiv2022

Identification of potential natural compound inhibitors and drug like molecules against human METTL3 by docking and molecular dynamics simulation

Nucleotide level chemical modification in transcriptome is critical in regulating different cellular processes, including cancer. The most investigated epitranscriptomic modification is methylation at the N6-position of adenosine (m6A). This dynamic modification process is carried out by: writer, reader and eraser proteins. Writers are methyltransferases, METTL3 is the major writer that works in association with METTL14, an accessory protein. Extensive study revealed that cancer progression for acute myeloid leukaemia, gastric cancer, colorectal cancer, hepatocellular carcinoma, and lung cancer is directly contributed by irregular expression of METTL3. Targeting METTL3, has opened a new window in the development of new inhibitors/drugs. In this study, 80 commercially available compounds were found from an unbiased screening by molecular docking, showing better score when compared with the existing substrate/substrate-analogue and the inhibitor bound crystal structures in terms of docking score and binding energy calculation. Among this pool of compounds, the best seven small molecules, AMF, RAD, JNJ, MEH, ECP, MHN, SGI, have been selected and further validated by different computational tools like binding energy calculation, molecular dynamics simulation etc. The novel hits found in this study can function as lead compounds which can be developed into inhibitors as well as drugs, specific against METTL3.

bioinformatics↗