Rajarshi Roy

@purdue.edu

Post-Doctoral Research Associate in Medicinal Chemistry and Molecular Pharmacology Department
Purdue University

EDUCATION

PhD (Biosciences and Biomedical Engineering) --- Indian Institute of Technology Indore: Indore, Madhya Pradesh, IN
Master of Science (Biophysics) --- University of Kalyani: Kalyani, West Bengal, IN
Bachelor of Science (Physics) --- University of Calcutta: Kolkata, West Bengal, IN

RESEARCH INTERESTS

Computational Biophysics, Molecular Dynamics

Scopus Publications

444

Scholar Citations

Scholar h-index

Scholar i10-index

Scopus Publications

The role of extrinsic and intrinsic factors in perceptual filling-in of the blind-spot with variegated color and texture stimuli
Amrita Mukherjee, Avijit Paul, Rajarshi Roy, and Kuntal Ghosh
Elsevier BV

Predicting immune response targets in orthoflaviviruses through sequence homology and computational analysis
Venkata N. Are, Rajarshi Roy, Sandeep Kumar Dhanda, Sanchit Neema, Neha Rani Sahu, Nitin Adithya, Ritudhwaj Tiwari, Parimal Kar, and Debasis Nayak
Springer Science and Business Media LLC

4″-Alkyl EGCG Derivatives Induce Cytoprotective Autophagy Response by Inhibiting EGFR in Glioblastoma Cells
Satyam Singh, Priya Ghosh, Rajarshi Roy, Ananyaashree Behera, Revathy Sahadevan, Parimal Kar, Sushabhan Sadhukhan, and Avinash Sonawane
American Chemical Society (ACS)

The conformational dynamics of Hepatitis C Virus E2 glycoprotein with the increasing number of N-glycosylation unraveled by molecular dynamics simulations
Sayan Poddar, Rajarshi Roy, and Parimal Kar
Informa UK Limited
The Hepatitis C Virus (HCV), responsible for causing hepatitis and a significant contributor to liver disorders, presents a challenge for treatment due to its high genetic variability. Despite efforts, there is still no effective medication available for this virus. One of the promising targets for drug development involves targeting glycoprotein E2. However, our understanding of the dynamic behavior of E2 and its associated glycans remains limited. In this study, we investigated the dynamic characteristics of E2 with varying degrees of glycosylation using all-atom molecular dynamics simulations. We also explored glycan's interactions with the protein and among themselves. An overall increase in correlation between the vital protein regions was observed with an increase in glycan number. The protein dynamics is followed by the analysis of glycan dynamics, where the flexibility of the individual glycans was analyzed in their free and bound state, which revealed a decrease in their fluctuation in some cases. Furthermore, we generated the free energy landscape of individual N-glycan linkages in both free and bound states and observed both increases and decreases in flexibility, which can be attributed to the formation and breakage of hydrogen bonds with amino acids. Finally, we found that for a high glycosylation system, glycans interact with glycoprotein and form hydrogen bonds among themselves. Moreover, the hydrogen bond profiles of a given glycan can vary when influenced by other glycans. In summary, our study provides valuable insights into the dynamics of the core region of HCV E2 glycoprotein and its associated glycans.Communicated by Ramaswamy H. Sarma.

Activation-induced cytidine deaminase an antibody diversification enzyme interacts with chromatin modifier UBN1 in B-cells
Ankit Jaiswal, Rajarshi Roy, Anubhav Tamrakar, Amit Kumar Singh, Parimal Kar, and Prashant Kodgire
Springer Science and Business Media LLC
AbstractActivation-induced cytidine deaminase (AID) is the key mediator of antibody diversification in activated B-cells by the process of somatic hypermutation (SHM) and class switch recombination (CSR). Targeting AID to the Ig genes requires transcription (initiation and elongation), enhancers, and its interaction with numerous factors. Furthermore, the HIRA chaperon complex, a regulator of chromatin architecture, is indispensable for SHM. The HIRA chaperon complex consists of UBN1, ASF1a, HIRA, and CABIN1 that deposit H3.3 onto the DNA, the SHM hallmark. We explored whether UBN1 interacts with AID using computational and in-vitro experiments. Interestingly, our in-silico studies, such as molecular docking and molecular dynamics simulation results, predict that AID interacts with UBN1. Subsequently, co-immunoprecipitation and pull-down experiments established interactions between UBN1 and AID inside B-cells. Additionally, a double immunofluorescence assay confirmed that AID and UBN1 were co-localized in the human and chicken B-cell lines. Moreover, proximity ligation assay studies validated that AID interacts with UBN1. Ours is the first report on the interaction of genome mutator enzyme AID with UBN1. Nevertheless, the fate of interaction between UBN1 and AID is yet to be explored in the context of SHM or CSR.

Computational studies indicated the effectiveness of human metabolites against SARS-Cov-2 main protease
Rajarshi Roy, Md Fulbabu Sk, Omprakash Tanwar, and Parimal Kar
Springer Science and Business Media LLC

Computational insights into VacA toxin inhibition: harnessing FDA-approved antibiotics against Helicobacter pylori
Dharmendra Kashyap, Suman Koirala, Rajarshi Roy, Vaishali Saini, Nidhi Varshney, Pranit Hemant Bagde, Sunanda Samanta, Parimal Kar, and Hem Chandra Jha
Informa UK Limited
Cancer is a condition in which a few of the body's cells grow beyond its control and spread to other outward regions. Globally, gastric cancer (GC) is third most common cause of cancer-related mortality and the fourth most common kind of cancer. Persistent infection of VacA-positive Helicobacter pylori (H. pylori) modulates cellular physiology and leads to GC. About ∼70% of H. pylori are positive for vacuolating cytotoxin-A (VacA), and it infects ∼80-90% of world populations. Herein, for first time, we repurposed FDA-approved gram-negative antibiotics, which are feasible alternatives to existing regimens and may be used in combinatorial treatment against VacA-positive H. pylori. Out of 110 FDA-approved antibiotics, we retrieved 92 structures, which were screened against the VacA protein. Moreover, we determined that the top eight hit antibiotics viz; cefpiramide, cefiderocol, eravacycline, doxycycline, ceftriaxone, enoxacin, tedizolid, and cefamandole show binding free energies of -9.1, -8.9, -8.1, -8.0, -7.9, -7.8, -7.8 and -7.8 Kcal/mol, respectively, with VacA protein. Finally, we performed 100 ns duplicate MD simulations on the top eight selected antibiotics showing strong VacA binding. Subsequently, five antibiotics, including cefiderocol, cefpiramide, doxycycline, enoxacin, and tedizolid show stable ligand protein distance and good binding affinity revealed by the MM-PBSA scheme. Among the five antibiotics cefiderocol act as the most potent inhibitor (-28.33 kcal/mol). Furthermore, we also identified the hotspot residue like Asn-506, Tyr-529, and Phe-483 which control the interaction. Concisely, we identified antibiotics that can be repurposed against VacA of H. pylori and explored their molecular mechanism of interaction with VacA.Communicated by Ramaswamy H. Sarma.

Elucidating the conformational dynamics of histo-blood group antigens and their interactions with the rotavirus spike protein through computational lens
Sayan Poddar, Rajarshi Roy, and Parimal Kar
Informa UK Limited
In the present study, we investigated the conformational dynamics of histo-blood group antigens (HBGAs) and their interactions with the VP8* domain of four rotavirus genotypes (P[4], P[6], P[19], and P[11]) utilizing all-atom molecular dynamics simulations in explicit water. Our study revealed distinct changes in the dynamic behavior of the same glycan due to linkage variations. We observed that LNFPI HBGA having a terminal β linkage shows two dominant conformations after complexation, whereas only one was obtained for LNFPI with a terminal α linkage. Interestingly, both variants displayed a single dominant structure in the free state. Similarly, LNT and LNnT show a shift in their dihedral linkage profile between their two terminal monosaccharides because of a change in the linkage from β(1-3) to β(1-4). The molecular mechanics generalized Born surface area (MM/GBSA) calculations yielded the highest binding affinity for LNFPI(β)/P[6] (-13.93 kcal/mol) due to the formation of numerous hydrogen bonds between VP8* and HBGAs. LNnT binds more strongly to P[11] (-12.88 kcal/mol) than LNT (-4.41 kcal/mol), suggesting a single change in the glycan linkage might impact its binding profile significantly. We have also identified critical amino acids and monosaccharides (Gal and GlcNAc) that contributed significantly to the protein-ligand binding through the per-residue decomposition of binding free energy. Moreover, we found that the interaction between the same glycan and different protein receptors within the same rotavirus genogroup influenced the micro-level dynamics of the glycan. Overall, our study helps a deeper understanding of the H-type HBGA and rotavirus spike protein interaction.Communicated by Ramaswamy H. Sarma.

Plant derived active compounds of ayurvedic neurological formulation, Saraswatharishta as a potential dual leucine zipper kinase inhibitor: an in-silico study
Suman Koirala, Rajarshi Roy, Sunanda Samanta, Subhasmita Mahapatra, and Parimal Kar
Informa UK Limited
Recent findings have highlighted the essential role of dual leucine zipper kinase (DLK) in neuronal degeneration. Saraswatharishta (SWRT), an ayurvedic formulation utilized in traditional Indian medicine, has demonstrated effectiveness in addressing neurodegenerative diseases. Herein, we aim to delve into the atomistic details of the mode of action of phytochemicals present in SWRT against DLK. Our screening process encompassed over 500 distinct phytochemicals derived from the main ingredients of the SWRT formulation. Through a comparative analysis of docking scores and relative poses, we successfully identified four novel compounds, which underwent further investigation via 2 × 500 ns long molecular dynamics (MD) simulations. Among the top four compounds, CID16066851 sourced from the Acorus calamus displayed the most stable complex with DLK. The molecular mechanics Poisson - Boltzmann surface area (MM-PBSA) calculations highlighted the significance of electrostatic and van der Waals interactions in the binding recognition process. Additionally, we identified key residues, namely Phe192, Leu243, Val139, and Leu141, as hotspots that predominantly govern the DLK-inhibitor interaction. Notably, the leading compounds are sourced from the Acorus calamus, Syzygium aromaticum, Zingiber officinale, and Anethum sowa plants present in the SWRT formulation. Overall, the findings of our study hold promise for future drug development endeavors combating neurodegenerative conditions.Communicated by Ramaswamy H. Sarma.

Withania somnifera extract reduces gastric cancerous properties through inhibition of gankyrin in cellular milieu produced by Helicobacter pylori and Epstein Barr virus
Dharmendra Kashyap, Rajarshi Roy, Nidhi Varshney, Budhadev Baral, Pranit Hemant Bagde, Meenakshi Kandpal, Sachin Kumar, Parimal Kar, and Hem Chandra Jha
Informa UK Limited
Helicobacter pylori and Epstein Barr virus (EBV) are group1 carcinogens and their role in Gastric cancer (GC) is well established. Previously we have shown that H. pylori and EBV appears to support aggressive gastric oncogenesis through the upregulation of oncoprotein Gankyrin. Natural plant active molecules have the potential to interrupt oncogenesis. Herein, we investigated the potential of Withania somnifera root extract (WSE) as a possible chemotherapeutic agent against host oncoprotein Gankyrin whose expression was altered by H. pylori and EBV-associated modified cellular milieu. The results show that WSE does not have any inhibitory effect on H. pylori and EBV-associated gene transcripts except for the lmps (lmp1, lmp2a, and lmp2B). Moreover, the WSE exert their anticancer activity via host cellular response and decreased the expression of cell-migratory (mmp3 and mmp7); cell-cycle regulator (pcna); antiapoptotic gene (bcl2); increased the expression of the proapoptotic gene (apaf1 and bax); and tumor suppressor (p53, prb, and pten). Knockdown of Gankyrin followed by the treatment of WSE also decreases the expression of TNF-ɑ, Akt, and elevated the expression of NFkB, PARP, Casp3, and Casp9. WSE also reduces cell migration, and genomic instability and forced the cells to commit programmed cell death. Moreover, molecular simulation studies revealed that out of eight active compounds of WSE, only four compounds such as withaferin A (WFA), withanoside IV (WA4), withanolide B (WNB), and withanolide D (WND) showed direct stable interaction with Gankyrin. This article reports for the first time that treatment of WSE decreased the cancerous properties through host cellular response modulation in gastric epithelial cells coinfected with H. pylori and EBV.Communicated by Ramaswamy H. Sarma.

Plant-derived active compounds as a potential nucleocapsid protein inhibitor of SARS-CoV-2: an in-silico study
Dharmendra Kashyap, Rajarshi Roy, Parimal Kar, and Hem Chandra Jha
Informa UK Limited
Abstract The coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2. This virus has a high mismatch repair proofreading ability due to its unique exonuclease activity, making it knotty to treat. The nucleocapsid protein can serve as a potential antiviral drug target, as this protein is responsible for multiple captious functions during the viral life cycle. Herein, we have investigated the potential to repurpose active antiviral compounds of plant origins for treating the SARS-CoV-2 infection. In the present study, we followed the molecular docking methodology to screen druggable natural plants’ active compounds against the nucleocapsid protein of SARS-CoV-2. The virtual screening of all 68 compounds revealed that the top seven active compounds, such as withanolide D, hypericin, silymarin, oxyacanthine, withaferin A, Acetyl aleuritolic acid, and rhein, exhibit good binding affinity with druggable ADME properties, toxicity, and Pass prediction. The stability of the docked complexes was studied by conducting molecular simulations of 100 ns. MM-GBSA calculated the binding free energy uncovered that withanolide D, hypericin, and silymarin result in highly stable binding conformations in three different sites of the nucleocapsid protein. However, further investigation is needed in order to validate the candidacy of these inhibitors for clinical trials. Communicated by Ramaswamy H. Sarma Highlights Natural plants’ active compounds may aid in the inhibition of SARS-CoV-2 replication and COVID-19 therapeutics. Hypericin, silymarin, withanolide D, oxyacanthine, withaferin A, Acetyl aleuritolic acid, and rhein are effective against SARS-CoV-2 N protein. Studied natural plants’ active compounds could be useful against COVID-19 and its associated organs comorbidities. ADMET properties of selected compounds favor these compounds as druggable candidates.

Conformational preferences of triantennary and tetraantennary hybrid N-glycans in aqueous solution: Insights from 20 μs long atomistic molecular dynamic simulations
Rajarshi Roy, Sayan Poddar, Md Fulbabu Sk, and Parimal Kar
Informa UK Limited
Abstract In the current study, we have investigated the conformational dynamics of a triantennary (N-glycan1) and tetraantennary (N-glycan2) hybrid N-glycans found on the surface of the HIV glycoprotein using 20 μs long all-atom molecular dynamics (MD) simulations. The main objective of the present study is to elucidate the influence of adding a complex branch on the overall glycan structural dynamics. Our investigation suggests that the average RMSD value increases when a complex branch is added to N-glycan1. However, the RMSD distribution is relatively wider in the case of N-glycan1 compared to N-glycan2, which indicates that multiple complex branches restrict the conformational variability of glycans. A similar observation is obtained from the principal component analysis of both glycans. All the puckering states (4C1 to 1C4) of each monosaccharide except mannose are sampled in our simulations, although the 4C1 chair form is energetically more favorable than 1C4. In N-glycan1, the 1–6 linkage in the mannose branch [Man(9)-α(1-6)-Man(5)] stays in the gauche-gauche cluster, whereas it moves towards trans-gauche in N-glycan2. For both glycans, mannose branches are more flexible than the complex branches, and adding a complex branch does not influence the dynamics of the mannose branches. We have noticed that the end-to-end distance of the complex branch shortens by ∼ 10 Å in the presence of another complex branch. This suggests that in the presence of an additional complex branch, the other complex branch adopts a close folded structure. All these conformational changes involve the selective formation of inter-residue and water-mediated hydrogen-bond networks. Communicated by Ramaswamy H. Sarma Graphical Abstract

Comparison of the conformational dynamics of an N-glycan in implicit and explicit solvents
Rajarshi Roy, Sayan Poddar, and Parimal Kar
Elsevier BV

Emerging Biomedical Applications of the Vesicular Stomatitis Virus Glycoprotein
Sheeba Rehman, Suman Bishnoi, Rajarshi Roy, Anshu Kumari, Harikrishnan Jayakumar, Sharad Gupta, Parimal Kar, Asit K. Pattnaik, and Debasis Nayak
American Chemical Society (ACS)
Nanoparticles (NPs) made of metals, polymers, micelles, and liposomes are increasingly being used in various biomedical applications. However, most of these NPs are hazardous for long- and short-term use and hence have restricted biomedical applications. Therefore, naturally derived, biocompatible, and biodegradable nanoconstructs are being explored for such applications. Inspired by the biology of viruses, researchers are exploring the viral proteins that hold considerable promise in biomedical applications. The viral proteins are highly stable and further amenable to suit specific biological applications. Among various viral proteins, vesicular stomatitis virus glycoprotein (VSV-G) has emerged as one of the most versatile platforms for biomedical applications. Starting with their first major use in lentivirus/retrovirus packaging systems, the VSV-G-based reagents have been tested for diverse biomedical use, many of which are at various stages of clinical trials. This manuscript discusses the recent advancements in the use of the VSV-G-based reagents in medical, biological research, and clinical applications particularly highlighting emerging applications in biomedical imaging.

Role of Doxorubicin on the Loading Efficiency of ICG within Silk Fibroin Nanoparticles
Saumya Jaiswal, Rajarshi Roy, Surjendu Bikash Dutta, Suman Bishnoi, Parimal Kar, Abhijeet Joshi, Debasis Nayak, and Sharad Gupta
American Chemical Society (ACS)
The effective loading or encapsulation of multimodal theranostic agents within a nanocarrier system plays an important role in the clinical development of cancer therapy. In recent years, the silk fibroin protein-based delivery system has been drawing significant attention to be used in nanomedicines due to its biocompatible and biodegradable nature. In this study, silk fibroin nanoparticles (SNPs) have been synthesized by a novel and cost-effective ultrasonic atomizer-based technique for the first time. The fabricated SNPs were coencapsulated by the FDA-approved indocyanine green (ICG) dye and the chemotherapeutic drug doxorubicin (DOX). The synthesized SNPs are spherical, with an average diameter of ∼37 ± 4 nm, and the ICG-DOX-coencapsulated SNPs (ID-SNPs) have a diameter size of ∼47 ± 6 nm. For the first time, here we demonstrate that DOX helps in the higher loading of ICG within the ID-SNPs, which enhances the encapsulation efficiency of ICG by ∼99%. This could be attributed to the interaction of ICG and DOX molecules with the silk fibroin protein, which helps ICG to get loaded more efficiently within these nanoparticles. The overall finding of this study suggests that the ID-SNPs could be utilized for enhanced ICG-complemented multimodal deep-tissue bioimaging and synergistic chemo-photothermal therapy.

Structure-based design and synthesis of a novel long-chain 4′′-alkyl ether derivative of EGCG as potent EGFR inhibitor: in vitro and in silico studies
Satyam Singh, Revathy Sahadevan, Rajarshi Roy, Mainak Biswas, Priya Ghosh, Parimal Kar, Avinash Sonawane, and Sushabhan Sadhukhan
Royal Society of Chemistry (RSC)
Among the synthesized 4′′-alkyl EGCG derivatives, 4′′-C14 EGCG inhibited EGF stimulated phosphorylation of EGFR and its downstream signaling pathways, ERK and Akt. 4′′-C14 EGCG showed significantly improved stability than EGCG and induced apoptosis.

Effect of Sulfation on the Conformational Dynamics of Dermatan Sulfate Glycosaminoglycan: A Gaussian Accelerated Molecular Dynamics Study
Rajarshi Roy, Nisha Amarnath Jonniya, and Parimal Kar
American Chemical Society (ACS)
Glycosaminoglycans (GAGs) are anionic biopolymers present on cell surfaces as a part of proteoglycans. The biological activities of GAGs depend on the sulfation pattern. In our study, we have considered three octadecasaccharide dermatan sulfate (DS) chains with increasing order of sulfation (dp6s, dp7s, and dp12s) to illuminate the role of sulfation on the GAG units and its chain conformation through 10 μs-long Gaussian accelerated molecular dynamics simulations. DS is composed of repeating disaccharide units of iduronic acid (IdoA) and N-acetylgalactosamine (N-GalNAc). Here, N-GalNAc is linked to IdoA via β(1-4), while IdoA is linked to N-GalNAc through α(1-3). With the increase in sulfation, the DS structure becomes more rigid and linear, as is evident from the distribution of root-mean-square deviations (RMSDs) and end-to-end distances. The tetrasaccharide linker region of the main chain shows a rigid conformation in terms of the glycosidic linkage. We have observed that upon sulfation (i.e., dp12s), the ring flip between two chair forms vanished for IdoA. The dynamic cross-correlation analysis reveals that the anticorrelation motions in dp12s are reduced significantly compared to dp6s or dp7s. An increase in sulfation generates relatively more stable hydrogen-bond networks, including water bridging with the neighboring monosaccharides. Despite the favorable linear structures of the GAG chains, our study also predicts few significant bendings related to the different puckering states, which may play a notable role in the function of the DS. The relation between the global conformation with the micro-level parameters such as puckering and water-mediated hydrogen bonds shapes the overall conformational space of GAGs. Overall, atomistic details of the DS chain provided in this study will help understand their functional and mechanical roles, besides developing new biomaterials.

Phosphorylation-Induced Conformational Dynamics and Inhibition of Janus Kinase 1 by Suppressors of Cytokine Signaling 1
Md Fulbabu Sk, Nisha Amarnath Jonniya, Rajarshi Roy, and Parimal Kar
American Chemical Society (ACS)
The dysfunction of the JAK/STAT (Janus kinase/signal transducers and activators of transcription) pathway results in several pathophysiological conditions, including autoimmune disorders. The negative feedback regulators of the JAK/STAT signaling pathway, suppressors of cytokine signaling (SOCS), act as a natural inhibitor of JAK and inhibit aberrant activity. SOCS1 is the most potent member of the SOCS family, whose kinase inhibitory region targets the substrate-binding groove of JAK with high affinity and blocks the phosphorylation of JAK kinases. Overall, we performed an aggregate of 13 μs molecular dynamics simulations on the activation loop's three different phosphorylation (double and single) states. Results from our simulations show that the single Tyr1034 phosphorylation could stabilize the JAK1/SOCS1 complex as well as the flexible activation segment. The phosphate-binding loop (P-loop) shows conformational variability at dual and single phosphorylated states. Principal component analysis and protein structure network (PSN) analysis reveal that the different phosphorylation states and SOCS1 binding induce intermediate inactive conformations of JAK1, which could be a better target for future JAK1 selective drug design. PSN analysis suggests that the com-pY1034 system is stabilized due to higher values of network hubs than the other two complex systems. Moreover, the binding free energy calculations suggest that pTyr1034 states show a higher affinity toward SOCS1 than the dual and pTyr1035 states. We believe that the mechanistic understanding of JAK1/SOCS1 complexation will aid future studies related to peptide inhibitors based on SOCS1.

Comparative Structural Dynamics of Isoforms of Helicobacter pylori Adhesin BabA Bound to Lewis b Hexasaccharide via Multiple Replica Molecular Dynamics Simulations
Rajarshi Roy, Nisha Amarnath Jonniya, Md Fulbabu Sk, and Parimal Kar
Frontiers Media SA
BabA of Helicobacter pylori is the ABO blood group antigen-binding adhesin. Despite considerable diversity in the BabA sequence, it shows an extraordinary adaptation in attachment to mucosal layers. In the current study, multiple replica molecular dynamics simulations were conducted in a neutral aqueous solution to elucidate the conformational landscape of isoforms of BabA bound to Lewis b (Leb) hexasaccharide. In addition, we also investigated the underlying molecular mechanism of the BabA-glycan complexation using the MM/GBSA scheme. The conformational dynamics of Leb in the free and protein-bound states were also studied. The carbohydrate-binding site across the four isoforms was examined, and the conformational variability of several vital loops was observed. The cysteine–cysteine loops and the two diversity loops (DL1 and DL2) were identified to play an essential role in recognizing the glycan molecule. The flexible crown region of BabA was stabilized after association with Leb. The outward movement of the DL2 loop vanished upon ligand binding for the Spanish specialist strain (S381). Our study revealed that the S831 strain shows a stronger affinity to Leb than other strains due to an increased favorable intermolecular electrostatic contribution. Furthermore, we showed that the α1-2-linked fucose contributed most to the binding by forming several hydrogen bonds with key amino acids. Finally, we studied the effect of the acidic environment on the BabA-glycan complexation via constant pH MD simulations, which showed a reduction in the binding free energy in the acidic environment. Overall, our study provides a detailed understanding of the molecular mechanism of Leb recognition by four isoforms of H. pylori that may help the development of therapeutics targeted at inhibiting H. pylori adherence to the gastric mucosa.

Unraveling the Molecular Mechanism of Recognition of Selected Next-Generation Antirheumatoid Arthritis Inhibitors by Janus Kinase 1
Md Fulbabu Sk, Nisha Amarnath Jonniya, Rajarshi Roy, and Parimal Kar
American Chemical Society (ACS)
Rheumatoid arthritis (RA) is a chronic immune-related condition, primarily of joints, and is highly disabling and painful. The inhibition of Janus kinase (JAK)-related cytokine signaling pathways using small molecules is prevalent nowadays. The JAK family belongs to nonreceptor cytoplasmic protein tyrosine kinases (PTKs), including JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2). JAK1 has received significant attention after being identified as a promising target for developing anti-RA therapeutics. Currently, no crystal structure is available for JAK1 in complex with the next-generation anti-RA drugs. In the current study, we investigated the mechanism of binding of baricitinib, filgotinib, itacitinib, and upadacitinib to JAK1 using a combined method of molecular docking, molecular dynamics simulation, and binding free energy calculation via the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) scheme. We found that the calculated binding affinity decreases in the order upadacitinib > itacitinib > filgotinib > baricitinib. Due to the increased favorable intermolecular electrostatic contribution, upadacitinib is more selective to JAK1 compared to the other three inhibitors. The cross-correlation and principal component analyses showed that different inhibitor bindings significantly affect the binding site dynamics of JAK1. Furthermore, our studies indicated that the hydrophobic residues and hydrogen bonds from the hinge region (Glu957 and Leu959) of JAK1 played an essential role in stabilizing the inhibitors. Protein structural network analysis reveals that the total number of links and hubs in JAK1/baricitinib (354, 48) is more significant than those in apo (328, 40) and the other three complexes. The JAK1/baricitinib complex shows the highest probability of the highest-ranked community, indicating a compact network of the JAK1/baricitinib complex, consistent with its higher stability than the rest of the four systems. Overall, our study may be crucial for the rational design of JAK1-selective inhibitors with better affinity.

Discovery of potential competitive inhibitors against With-No-Lysine kinase 1 for treating hypertension by virtual screening, inverse pharmacophore-based lead optimization, and molecular dynamics simulations
N.A. Jonniya, M.F. Sk, R. Roy, and P. Kar
Informa UK Limited
ABSTRACT The With-No-Lysine (WNK) has received attention because of its involvement in hypertension. Genetic mutation in the genes of WNK, leading to its overexpression, has been reported in Familial Hyperkalaemic Hypertension, and thus WNK is considered a potential drug target. Herein, we have performed a high-throughput virtual screening of ~11,000 compounds, mainly the natural phytochemical compounds and kinase inhibitory libraries, to find potential competitive inhibitors against WNK1. Initially, candidates with a docking score of ~ −10.0 kcal/mol or less were selected to further screen their good pharmacological properties by applying absorption, distribution, metabolism, excretion, and toxicity (ADMET). Finally, six docked compounds bearing appreciable binding affinities and WNK1 selectivity were complimented with 500 ns long all-atom molecular dynamic simulations. Subsequently, the MMPBSA scheme (Molecular Mechanics Poisson Boltzmann Surface Area) suggested three phytochemical compounds, C00000947, C00020451, and C00005031, with favourable binding affinity against WNK1. Among them, C00000947 acts as the most potent competitive inhibitor of WNK1. Further, inverse pharmacophore-based lead optimization of the C00000947 leads to one potential compound, meciadanol, which shows better binding affinity and specificity than C00000947 towards WNK1, which may be further exploited to develop effective therapeutics against WNK1-associated hypertension after in vitro and in vivo validation.

Finding potent inhibitors against SARS-CoV-2 main protease through virtual screening, ADMET, and molecular dynamics simulation studies
Rajarshi Roy, Md Fulbabu Sk, Nisha Amarnath Jonniya, Sayan Poddar, and Parimal Kar
Informa UK Limited
Abstract Currently, no antiviral drug or vaccine is available to treat COVID-19 caused by SARS-CoV-2. This underscores an urgent need for developing a drug against SARS-CoV-2. The main protease (3CLpro) of SARS-CoV-2 is considered an essential protein for maintaining the viral life cycle and, therefore, a potential target for drug development. In a recent study, 1000 potential ligands were identified for 3CLpro by screening 1.3 billion compounds from the ZINC15 library. In the current study, we have further screened these 1000 compounds using structure-based virtual screening utilizing the Schrödinger suite and identified nine compounds having a docking score of ∼ −11.0 kcal/mol or less. The top 5 hits display good pharmacological profiles revealing better absorption, proper permeability across the membrane, uniform distribution, and non-toxic. The molecular docking study is further complemented by molecular dynamics simulations of the top 5 docked complexes. The binding free energy analyses via the molecular mechanics generalized Born surface area (MM/GBSA) scheme reveals that ZINC000452260308 is the most potent (ΔGbind = −14.31 kcal/mol) inhibitor. The intermolecular van der Waals interactions mainly drive the 3CLpro-ligand association. This new compound may have great potential as a lead molecule to develop a new antiviral drug to fight against COVID-19. Communicated by Ramaswamy H. Sarma

Investigating the mechanism of recognition and structural dynamics of nucleoprotein-RNA complex from Peste des petits ruminants virus via Gaussian accelerated molecular dynamics simulations
Rajarshi Roy, Anurag Mishra, Sayan Poddar, Debasis Nayak, and Parimal Kar
Informa UK Limited
Abstract The nucleocapsid (N) protein from Peste des petits ruminants virus enwraps the nascent genomic RNA primarily to protect it from cellular enzymatic degradation. Here, we have combined molecular modeling and 1 μs long Gaussian accelerated molecular dynamics simulations to study the structural and conformational properties of the apo N-protein and three protein-RNA complexes, namely wild type (WT), MT1 (I46T/E297D/G342E), and MT2 (I46T/E297D/G342E/W333G). The root-mean-squared deviation (RMSD) analysis reveals that although MT2 deviates most significantly from the initial structure, the RNA binding region is more stable compared to WT or MT1. Further, the flexible nature of the N protein is revealed from the principal component analysis. Our study shows that the solvent accessible surface area of the binding region increases drastically for both mutant complexes compared to WT. The dynamic cross-correlation analysis suggests that the overall anticorrelated motion weakens after the RNA binding. MT2 displays a relatively larger positive correlation than WT or MT1. The binding free energy is estimated for all three complexes via the molecular mechanics/generalized Born surface (MM/GBSA) scheme, and it decreases in the order WT > MT1 > MT2. In all cases, the protein-RNA binding is mainly driven by the van der Waals interactions since the intermolecular electrostatic interaction is overcompensated by desolvation energy. All hotspot residues are identified from the per-residue decomposition of the total binding free energy. In MT2, RNA contributes most favorably compared to WT or MT1. We believe our study will help in understanding the mechanism of RNA recognition by N proteins. Communicated by Ramaswamy H. Sarma

Unraveling the Molecular Mechanism of Recognition of Human Interferon-Stimulated Gene Product 15 by Coronavirus Papain-Like Proteases: A Multiscale Simulation Study
Rajarshi Roy, Nisha Amarnath Jonniya, Sayan Poddar, Md Fulbabu Sk, and Parimal Kar
American Chemical Society (ACS)
The papain-like protease (PLpro) of the coronavirus (CoV) family plays an essential role in processing the viral polyprotein and immune evasion. Additional proteolytic activities of PLpro include deubiquitination and deISGylation, which can reverse the post-translational modification of cellular proteins conjugated with ubiquitin or (Ub) or Ub-like interferon-stimulated gene product 15 (ISG15). These activities regulate innate immune responses against viral infection. Thus, PLpro is a potential antiviral target. Here, we have described the structural and energetic basis of recognition of PLpro by the human ISG15 protein (hISG15) using atomistic molecular dynamics simulation across the CoV family, i.e., MERS-CoV (MCoV), SARS-CoV (SCoV), and SARS-CoV-2 (SCoV2). The cumulative simulation length for all trajectories was 32.0 μs. In the absence of the complete crystal structure of complexes, protein–protein docking was used. A mutation (R167E) was introduced across all three PLpro to study the effect of mutation on the protein–protein binding. Our study reveals that the apo-ISG15 protein remains closed while it adopts an open conformation when bound to PLpro, although the degree of openness varies across the CoV family. The binding free energy analysis suggests that hISG15 binds more strongly with SCoV2-PLpro compared to SCoV or MCoV. The intermolecular electrostatic interaction drives the hISG15-PLpro complexation. Our study showed that SCoV or MCoV-PLpro binds more strongly with the C-domain of hISG15, while SCoV2-PLpro binds more favorably the N-domain of hISG15. Overall, our study explains the molecular basis of differential deISGylating activities of PLpro among the CoV family and the specificity of SCoV2-PLpro toward hISG15.

An in-silico study on selected organosulfur compounds as potential drugs for SARS-CoV-2 infection via binding multiple drug targets
Liya Thurakkal, Satyam Singh, Rajarshi Roy, Parimal Kar, Sushabhan Sadhukhan, and Mintu Porel
Elsevier BV

RECENT SCHOLAR PUBLICATIONS

Computational insights into VacA toxin inhibition: harnessing FDA-approved antibiotics against Helicobacter pylori
D Kashyap, S Koirala, R Roy, V Saini, N Varshney, PH Bagde, S Samanta, ...
Journal of Biomolecular Structure and Dynamics 42 (24), 13725-13737 2024

Elucidating the conformational dynamics of histo-blood group antigens and their interactions with the rotavirus spike protein through computational lens
S Poddar, R Roy, P Kar
Journal of Biomolecular Structure and Dynamics 42 (23), 13201-13215 2024

Withania somnifera extract reduces gastric cancerous properties through inhibition of gankyrin in cellular milieu produced by Helicobacter pylori and Epstein Barr
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Plant derived active compounds of ayurvedic neurological formulation, Saraswatharishtaas a potential dual leucine zipper kinase inhibitor: an in-silico study
S Koirala, R Roy, S Samanta, S Mahapatra, P Kar
Journal of Biomolecular Structure and Dynamics 42 (20), 11201-11214 2024

The role of extrinsic and intrinsic factors in perceptual filling-in of the blind-spot with variegated color and texture stimuli
A Mukherjee, A Paul, R Roy, K Ghosh
Vision Research 222, 108452 2024

Predicting immune response targets in orthoflaviviruses through sequence homology and computational analysis
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Journal of Molecular Modeling 30 (8), 295 2024

The conformational dynamics of Hepatitis C Virus E2 glycoprotein with the increasing number of N-glycosylation unraveled by molecular dynamics simulations
S Poddar, R Roy, P Kar
Journal of Biomolecular Structure and Dynamics, 1-16 2024

4 ″-Alkyl EGCG Derivatives Induce Cytoprotective Autophagy Response by Inhibiting EGFR in Glioblastoma Cells
S Singh, P Ghosh, R Roy, A Behera, R Sahadevan, P Kar, S Sadhukhan, ...
ACS omega 9 (2), 2286-2301 2024

Activation-induced cytidine deaminase an antibody diversification enzyme interacts with chromatin modifier UBN1 in B-cells
A Jaiswal, R Roy, A Tamrakar, AK Singh, P Kar, P Kodgire
Scientific Reports 13 (1), 19615 2023

Computational studies indicated the effectiveness of human metabolites against SARS-Cov-2 main protease
R Roy, MF Sk, O Tanwar, P Kar
Molecular Diversity 27 (4), 1587-1602 2023

Plant-derived active compounds as a potential nucleocapsid protein inhibitor of SARS-CoV-2: an in-silico study
D Kashyap, R Roy, P Kar, HC Jha
Journal of Biomolecular Structure and Dynamics 41 (10), 4770-4785 2023

Conformational preferences of triantennary and tetraantennary hybrid N-glycans in aqueous solution: Insights from 20 μs long atomistic molecular dynamic simulations
R Roy, S Poddar, MF Sk, P Kar
Journal of Biomolecular Structure and Dynamics 41 (8), 3305-3320 2023

Asymmetric Perceptual Filling-In of Blind-Spot Through Novel Stimuli with Variegated Color and Texture Gradient
A Mukherjee, A Paul, R Roy, K Ghosh
Available at SSRN 4439324 2023

Comparison of the conformational dynamics of an N-glycan in implicit and explicit solvents
R Roy, S Poddar, P Kar
Carbohydrate Research 522, 108700 2022

Finding potent inhibitors against SARS-CoV-2 main protease through virtual screening, ADMET, and molecular dynamics simulation studies
R Roy, MF Sk, NA Jonniya, S Poddar, P Kar
Journal of Biomolecular Structure and Dynamics 40 (14), 6556-6568 2022

Emerging biomedical applications of the vesicular stomatitis virus glycoprotein
S Rehman, S Bishnoi, R Roy, A Kumari, H Jayakumar, S Gupta, P Kar, ...
ACS omega 7 (37), 32840-32848 2022

Role of doxorubicin on the loading efficiency of ICG within silk fibroin nanoparticles
S Jaiswal, R Roy, SB Dutta, S Bishnoi, P Kar, A Joshi, D Nayak, S Gupta
ACS Biomaterials Science & Engineering 8 (7), 3054-3065 2022

Effect of Sulfation on the Conformational Dynamics of Dermatan Sulfate Glycosaminoglycan: A Gaussian Accelerated Molecular Dynamics Study
R Roy, NA Jonniya, P Kar
The Journal of Physical Chemistry B 126 (21), 3852-3866 2022

Comparative Structural Dynamics of Isoforms of Helicobacter pylori Adhesin BabA Bound to Lewis b Hexasaccharide via Multiple Replica Molecular Dynamics
R Roy, NA Jonniya, MF Sk, P Kar
Frontiers in Molecular Biosciences 9, 852895 2022

Phosphorylation-induced conformational dynamics and inhibition of Janus Kinase 1 by suppressors of cytokine signaling 1
MF Sk, NA Jonniya, R Roy, P Kar
The Journal of Physical Chemistry B 126 (17), 3224-3239 2022

MOST CITED SCHOLAR PUBLICATIONS

Elucidating biophysical basis of binding of inhibitors to SARS-CoV-2 main protease by using molecular dynamics simulations and free energy calculations
MF Sk, R Roy, NA Jonniya, S Poddar, P Kar
Journal of Biomolecular Structure and Dynamics 39 (10), 3649-3661 2021
Citations: 84

Exploring the potency of currently used drugs against HIV-1 protease of subtype D variant by using multiscale simulations
MF Sk, R Roy, P Kar
Journal of Biomolecular Structure and Dynamics 39 (3), 988-1003 2021
Citations: 47

An in-silico study on selected organosulfur compounds as potential drugs for SARS-CoV-2 infection via binding multiple drug targets
L Thurakkal, S Singh, R Roy, P Kar, S Sadhukhan, M Porel
Chemical physics letters 763, 138193 2021
Citations: 47

Computational investigation of structural dynamics of SARS-CoV-2 methyltransferase-stimulatory factor heterodimer nsp16/nsp10 bound to the cofactor SAM
MF Sk, NA Jonniya, R Roy, S Poddar, P Kar
Frontiers in Molecular Biosciences 7, 590165 2020
Citations: 44

Investigating conformational dynamics of Lewis Y oligosaccharides and elucidating blood group dependency of cholera using molecular dynamics
R Roy, B Ghosh, P Kar
ACS omega 5 (8), 3932-3942 2020
Citations: 36

Investigating the mechanism of recognition and structural dynamics of nucleoprotein-RNA complex from Peste des petits ruminants virus via Gaussian accelerated
R Roy, A Mishra, S Poddar, D Nayak, P Kar
Journal of Biomolecular Structure and Dynamics 40 (5), 2302-2315 2022
Citations: 28

Structure-based design and synthesis of a novel long-chain 4′′-alkyl ether derivative of EGCG as potent EGFR inhibitor: In vitro and in silico studies
S Singh, R Sahadevan, R Roy, M Biswas, P Ghosh, P Kar, A Sonawane, ...
RSC advances 12 (28), 17821-17836 2022
Citations: 16

Unraveling the molecular mechanism of recognition of selected next-generation antirheumatoid arthritis inhibitors by Janus kinase 1
MF Sk, NA Jonniya, R Roy, P Kar
ACS omega 7 (7), 6195-6209 2022
Citations: 14

Unraveling the molecular mechanism of recognition of human interferon-stimulated gene product 15 by coronavirus papain-like proteases: A multiscale simulation study
R Roy, NA Jonniya, S Poddar, MF Sk, P Kar
Journal of Chemical Information and Modeling 61 (12), 6038-6052 2021
Citations: 11

Emerging biomedical applications of the vesicular stomatitis virus glycoprotein
S Rehman, S Bishnoi, R Roy, A Kumari, H Jayakumar, S Gupta, P Kar, ...
ACS omega 7 (37), 32840-32848 2022
Citations: 8

Computational studies indicated the effectiveness of human metabolites against SARS-Cov-2 main protease
R Roy, MF Sk, O Tanwar, P Kar
Molecular Diversity 27 (4), 1587-1602 2023
Citations: 7

Investigating potency of TMC-126 against wild-type and mutant variants of HIV-1 protease: a molecular dynamics and free energy study
MF Sk, S Haridev, R Roy, P Kar
SAR and QSAR in Environmental Research 32 (11), 941-962 2021
Citations: 6