Nisha Amarnath Jonniya
@ucsd.edu
PostDoctoral Employee
University of California San Diego, USA
EDUCATION
PhD in Computational Biology from Indian Institute of Technology Indore
M.Tech in Bioinformatics from Maulana Azad National Institute of Technology Bhopal
B.Tech in Biotechnology from National Institute of Technology Raipur
RESEARCH INTERESTS
Computational Biology, Biophysics, Drug Design, Bioinformatics
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Nisha Amarnath Jonniya, Sayan Poddar, Subhasmita Mahapatra, and Parimal Kar
Springer Science and Business Media LLC
Subhasmita Mahapatra, Nisha Amarnath Jonniya, Suman Koirala, and Parimal Kar
Informa UK Limited
The Fibroblast Growth Factor Receptor1 (FGFR1) kinase wields exquisite control on cell fate, proliferation, differentiation, and homeostasis. An imbalance of FGFR1 signaling leads to several pathogeneses of diseases ranging from multiple cancers to allergic and neurodegenerative disorders. In this study, we investigated the phosphorylation-induced conformational dynamics of FGFR1 in apo and ATP-bound states via all-atom molecular dynamics simulations. All simulations were performed for 2 × 2 µs. We have also investigated the energetics of the binding of ATP to FGFR1 using the molecular mechanics Poisson-Boltzmann scheme. Our study reveals that the FGFR1 kinase can reach a fully active configuration through phosphorylation and ATP binding. A 3-10 helix formation in the activation loop signifies its rearrangement leading to stability upon ATP binding. The interaction of phosphorylated tyrosine (pTyr654) with positively charged residues forms strong salt-bridge interactions, driving the compactness of the structure. The dynamic cross-correlation map reveals phosphorylation enhances correlated motions and reduces anti-correlated motions between different domains. We believe that the mechanistic understanding of large-conformational changes upon the activation of the FGFR1 kinase will aid the development of novel targeted therapeutics.Communicated by Ramaswamy H. Sarma.
Subhasmita Mahapatra, Nisha Amarnath Jonniya, Suman Koirala, Kapil Dattatray Ursal, and Parimal Kar
Informa UK Limited
ABSTRACT Fibroblast Growth Factor (FGF) ligands and their receptors are crucial factors driving chemoresistance in several malignancies, challenging the efficacy of currently available anti-cancer drugs. The Fibroblast growth factor/receptor (FGF/FGFR) signalling malfunctions in tumor cells, resulting in a range of molecular pathways that may impact its drug effectiveness. Deregulation of cell signalling is critical since it can enhance tumor growth and metastasis. Overexpression and mutation of FGF/FGFR induce regulatory changes in the signalling pathways. Chromosomal translocation facilitating FGFR fusion production aggravates drug resistance. Apoptosis is inhibited by FGFR-activated signalling pathways, reducing multiple anti-cancer medications' destructive impacts. Angiogenesis and epithelial-mesenchymal transition (EMT) are facilitated by FGFRs-dependent signalling, which correlates with drug resistance and enhances metastasis. Further, lysosome-mediated drug sequestration is another prominent method of resistance. Inhibition of FGF/FGFR by following a plethora of therapeutic approaches such as covalent and multitarget inhibitors, ligand traps, monoclonal antibodies, recombinant FGFs, combination therapy, and targeting lysosomes and micro RNAs would be helpful. As a result, FGF/FGFR suppression treatment options are evolving nowadays. To increase positive impacts, the processes underpinning the FGF/FGFR axis' role in developing drug resistance need to be clarified, emphasizing the need for more studies to develop novel therapeutic options to address this significant problem. Communicated by Ramaswamy H. Sarma.
Nisha Amarnath Jonniya and Parimal Kar
American Chemical Society (ACS)
Dengue virus, a flavivirus that causes dengue shock syndrome and dengue hemorrhagic fever, is currently prevalent worldwide. A two-component protease (NS2B-NS3) is essential for maturation, representing an important target for designing anti-flavivirus drugs. Previously, consideration has been centered on developing active-site inhibitors of NS2B-NS3pro. However, the flat and charged nature of its active site renders difficulties in developing inhibitors, suggesting an alternative strategy for identifying allosteric inhibitors. The allosterically sensitive site of the dengue protease is located near Ala125, between the 120s loop and 150s loop. Using atomistic molecular dynamics simulations, we have explored the protease's conformational dynamics upon binding of an allosteric inhibitor. Furthermore, characterization of the inherent flexible loops (71-75s loop, 120s loop, and 150s loop) is carried out for allosteric-inhibitor-bound wild-type and mutant A125C variants and a comparison is performed with its unbound state to extract the structural changes describing the inactive state of the protease. Our study reveals that compared to the unliganded system, the inhibitor-bound system shows large structural changes in the 120s loop and 150s loop in contrast to the rigid 71-75s loop. The unliganded system shows a closed-state pocket in contrast to the open state for the wild-type complex that locks the protease into the open and inactive-state conformations. However, the mutant complex fluctuates between open and closed states. Also, we tried to see how mutation and binding of an allosteric inhibitor perturb the connectivity in a protein structure network (PSN) at contact levels. Altogether, our study reveals the mechanism of conformational rearrangements of loops at the molecular level, locking the protein in an inactive conformation, which may be useful for developing allosteric inhibitors.
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.
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.
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.
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.
Omkar Indari, Md Fulbabu Sk, Shweta Jakhmola, Nisha Amarnath Jonniya, Hem Chandra Jha, and Parimal Kar
American Chemical Society (ACS)
Malaria causes millions of deaths every year. The malaria parasite spends a substantial part of its life cycle inside human erythrocytes. Inside erythrocytes, it synthesizes and displays various proteins onto the erythrocyte surface, such as Plasmodium falciparum erythrocytic membrane protein-1 (PfEMP1). This protein contains cysteine-rich interdomain region (CIDR) domains which have many subtypes based on sequence diversity and can cross-talk with host molecules. The CIDRα1.4 subtype can attach host endothelial protein C receptor (EPCR). This interaction facilitates infected erythrocyte adherence to brain endothelium and subsequent development of cerebral malaria. Through molecular dynamics simulations in conjunction with the molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) method, we explored the mechanism of interaction in the CIDRα1-EPCR complex. We examined the structural behavior of two CIDRα1 molecules (encoded by HB3-isolate var03-gene and IT4-isolate var07-gene) with EPCR unbound and bound (complex) forms. HB3var03CIDRα1 in apo and complexed with EPCR was comparatively more stable than IT4var07CIDRα1. Both of the complexes adopted two distinct conformational energy states. The hydrophobic residues played a crucial role in the binding of both complexes. For HB3var03CIDRα1-EPCR, the dominant energetic components were total polar interactions, while in IT4var07CIDRα1-EPCR, the primary interaction was van der Waals and nonpolar solvation energy. The study also revealed details such as correlated conformational motions and secondary structure evolution. Further, it elucidated various hotspot residues involved in protein-protein recognition. Overall, our study provides additional information on the structural behavior of CIDR molecules in unbound and receptor-bound states, which will help to design potent inhibitors.
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.
Shruti Pyasi, Nisha Amarnath Jonniya, Md Fulbabu Sk, Debasis Nayak, and Parimal Kar
Informa UK Limited
Abstract The bovine ephemeral fever virus (BEFV) is an enzootic agent that affects millions of bovines and causes major economic losses. Though the virus is seasonally reported with a very high morbidity rate (80–100%) from African, Australian, and Asiatic continents, it remains a neglected pathogen in many of its endemic areas, with no proper therapeutic drugs or vaccines presently available for treatment. The RNA-dependent RNA polymerase (RdRp) catalyzes the viral RNA synthesis and is an appropriate candidate for antiviral drug developments. We utilized integrated computational tools to build the 3D model of BEFV-RdRp and then predicted its probable active binding sites. The virtual screening and optimization against these active sites, using several small-molecule inhibitors from a different category of Life Chemical database and FDA-approved drugs from the ZINC database, was performed. We found nine molecules that have docking scores varying between −6.84 to −10.43 kcal/mol. Furthermore, these complexes were analyzed for their conformational dynamics and thermodynamic stability using molecular dynamics simulations in conjunction with the molecular mechanics generalized Born surface area (MM-GBSA) scheme. The binding free energy calculations depict that the electrostatic interactions play a dominant role in the RdRp-inhibitor binding. The hot spot residues, such as Arg565, Asp631, Glu633, Asp740, and Glu707, were found to control the RdRp-inhibitor interaction. The ADMET analysis strongly suggests favorable pharmacokinetics of these compounds that may prove useful for treating the BEFV ailment. Overall, we anticipate that these findings would help explore and develop a wide range of anti-BEFV therapy. Communicated by Ramaswamy H. Sarma
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
Nisha Amarnath Jonniya, Md Fulbabu Sk, and Parimal Kar
Informa UK Limited
Abstract The with-no-lysine (WNK) kinase causes pseudohypoaldosteronism type II, a genetic form of hypertension. Due to ∼80% similarity among four isoforms (WNK1/2/3/4) of the WNK protein family, the discovery of an ATP-competitive inhibitor renders a significant challenge. Here, we combined molecular modeling and molecular dynamics simulations to study the structural and conformational properties of the WNK kinase isoforms bound to an ATP competitive inhibitor (WNK463). We have also investigated the effect of phosphorylation on the conformational properties of each isoform. The largest deviation of Cα atoms is observed for the unphosphorylated uWNK4 complex, while the least deviation is obtained for uWNK3. The G-loop and αC-helix regions are also more flexible in uWNK4 compared to the other three unphosphorylated isoforms. However, in uWNK1, the A-loop region is the most flexible compared to other complexes. In all cases, phosphorylation stabilizes different regions of the protein–inhibitor complexes. In the case of uWNK4, relatively higher anti-correlated motions are observed compared to the other three unphosphorylated complexes. Furthermore, in the case of uWNK4, the distance between N- and C-lobes is found to be slightly higher than other complexes. This distance is reduced in all four complexes after the phosphorylation. Principal component analyses suggest that the phosphorylation leads to structural stabilization in WNK1 and WNK4, while it causes more flexibility in WNK2 and WNK3. Overall, our study provides comprehensive and comparative information on the structural dynamics of the WNK isoform family with the known competitive inhibitor that would aid in the development of a new inhibitor. Communicated by Ramaswamy H. Sarma
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.
Nisha Amarnath Jonniya, Jinwei Zhang, and Parimal Kar
American Chemical Society (ACS)
The oxidative-stress-responsive kinase 1 (OSR1) and the STE20/SPS1-related proline-alanine-rich kinase (SPAK) are physiological substrates of the with-no-lysine (WNK) kinase. They are the master regulators of cation Cl- cotransporters that could be targeted for discovering novel antihypertensive agents. Both kinases have a conserved carboxy-terminal (CCT) domain that recognizes a unique peptide motif (Arg-Phe-Xaa-Val) present in their upstream kinases and downstream substrates. Here, we have combined molecular docking with molecular dynamics simulations and free-energy calculations to identify potential inhibitors that can bind to the allosteric pocket of the OSR1-CCT domain and impede its interaction with the WNK peptide. Our study revealed that STOCK1S-14279 and Closantel bound strongly to the allosteric pocket of OSR1 and displaced the WNK peptide from the primary pocket of OSR1. We showed that primarily Arg1004 and Gln1006 of the WNK4-peptide motif were involved in strong H-bond interactions with Glu453 and Arg451 of OSR1. Besides, our study revealed that atoms of Arg1004 were solvent-exposed in cases of STOCK1S-14279 and Closantel, implying that the WNK4 peptide was moved out of the pocket. Overall, the predicted potential inhibitors altogether abolish the OSR1-WNK4-peptide interaction, suggesting their potency as a prospective allosteric inhibitor against OSR1.
Shweta Jakhmola, Nisha Amarnath Jonniya, Md Fulbabu Sk, Annu Rani, Parimal Kar, and Hem Chandra Jha
American Chemical Society (ACS)
Epstein-Barr virus (EBV), a known tumorigenic virus, is associated with various neuropathies, including multiple sclerosis (MS). However, there is no anti-EBV FDA-approved drug available in the market. Our study targeted EBV protein EBV nuclear antigen 1 (EBNA1), crucial in virus replication and expressed in all the stages of viral latencies. This dimeric protein binds to an 18 bp palindromic DNA sequence and initiates the process of viral replication. We chose phytochemicals and FDA-approved MS drugs based on literature survey followed by their evaluation efficacies as anti-EBNA1 molecules. Molecular docking revealed FDA drugs ozanimod, siponimod, teriflunomide, and phytochemicals; emodin; protoapigenone; and EGCG bound to EBNA1 with high affinities. ADMET and Lipinski's rule analysis of the phytochemicals predicted favorable druggability. We supported our assessments of pocket druggability with molecular dynamics simulations and binding affinity predictions by the molecular mechanics generalized Born surface area (MM/GBSA) method. Our results establish a stable binding for siponimod and ozanimod with EBNA1 mainly via van der Waals interactions. We identified hot spot residues like I481', K477', L582', and K586' in the binding of ligands. In particular, K477' at the amino terminal of EBNA1 is known to establish interaction with two bases at the major groove of the DNA. Siponimod bound to EBNA1 engaging K477', thus plausibly making it unavailable for DNA interaction. Computational alanine scanning further supported the significant roles of K477', I481', and K586' in the binding of ligands with EBNA1. Conclusively, the compounds showed promising results to be used against EBNA1.
Shruti Pyasi, Vinita Sharma, Kumari Dipti, Nisha Amarnath Jonniya, and Debasis Nayak
MDPI AG
Bovine ephemeral fever virus (BEFV) is an overlooked pathogen, recently gaining widespread attention owing to its associated enormous economic impacts affecting the global livestock industries. High endemicity with rapid spread and morbidity greatly impacts bovine species, demanding adequate attention towards BEFV prophylaxis. Currently, a few suboptimum vaccines are prevailing, but were confined to local strains with limited protection. Therefore, we designed a highly efficacious multi-epitope vaccine candidate targeted against the geographically distributed BEFV population. By utilizing immunoinformatics technology, all structural proteins were targeted for B- and T-cell epitope prediction against the entire allele population of BoLA molecules. Prioritized epitopes were adjoined by linkers and adjuvants to effectively induce both cellular and humoral immune responses in bovine. Subsequently, the in silico construct was characterized for its physicochemical parameters, high immunogenicity, least allergenicity, and non-toxicity. The 3D modeling, refinement, and validation of ligand (vaccine construct) and receptor (bovine TLR7) then followed molecular docking and molecular dynamic simulation to validate their stable interactions. Moreover, in silico cloning of codon-optimized vaccine construct in the prokaryotic expression vector (pET28a) was explored. This is the first time HTL epitopes have been predicted using bovine datasets. We anticipate that the designed construct could be an effective prophylactic remedy for the BEF disease that may pave the way for future laboratory experiments.
Nisha Amarnath Jonniya, Md Fulbabu Sk, and Parimal Kar
Royal Society of Chemistry (RSC)
The binding of an allosteric inhibitor in WNK1 leads to the inactive state.
Md Fulbabu Sk, Rajarshi Roy, Nisha Amarnath Jonniya, Sayan Poddar, and Parimal Kar
Informa UK Limited
Abstract The recent outbreak of novel “coronavirus disease 2019” (COVID-19) has spread rapidly worldwide, causing a global pandemic. In the present work, we have elucidated the mechanism of binding of two inhibitors, namely α-ketoamide and Z31792168, to SARS-CoV-2 main protease (Mpro or 3CLpro) by using all-atom molecular dynamics simulations and free energy calculations. We calculated the total binding free energy (ΔGbind) of both inhibitors and further decomposed ΔGbind into various forces governing the complex formation using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Our calculations reveal that α-ketoamide is more potent (ΔGbind= − 9.05 kcal/mol) compared to Z31792168 (ΔGbind= − 3.25 kcal/mol) against COVID-19 3CLpro. The increase in ΔGbind for α-ketoamide relative to Z31792168 arises due to an increase in the favorable electrostatic and van der Waals interactions between the inhibitor and 3CLpro. Further, we have identified important residues controlling the 3CLpro-ligand binding from per-residue based decomposition of the binding free energy. Finally, we have compared ΔGbind of these two inhibitors with the anti-HIV retroviral drugs, such as lopinavir and darunavir. It is observed that α-ketoamide is more potent compared to lopinavir and darunavir. In the case of lopinavir, a decrease in van der Waals interactions is responsible for the lower binding affinity compared to α-ketoamide. On the other hand, in the case of darunavir, a decrease in the favorable intermolecular electrostatic and van der Waals interactions contributes to lower affinity compared to α-ketoamide. Our study might help in designing rational anti-coronaviral drugs targeting the SARS-CoV-2 main protease. Communicated by Ramaswamy H. Sarma
Md Fulbabu Sk, Nisha Amarnath Jonniya, Rajarshi Roy, Sayan Poddar, and Parimal Kar
Frontiers Media SA
Recently, a highly contagious novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has emerged, posing a global threat to public health. Identifying a potential target and developing vaccines or antiviral drugs is an urgent demand in the absence of approved therapeutic agents. The 5′-capping mechanism of eukaryotic mRNA and some viruses such as coronaviruses (CoVs) are essential for maintaining the RNA stability and protein translation in the virus. SARS-CoV-2 encodes S-adenosyl-L-methionine (SAM) dependent methyltransferase (MTase) enzyme characterized by nsp16 (2′-O-MTase) for generating the capped structure. The present study highlights the binding mechanism of nsp16 and nsp10 to identify the role of nsp10 in MTase activity. Furthermore, we investigated the conformational dynamics and energetics behind the binding of SAM to nsp16 and nsp16/nsp10 heterodimer by employing molecular dynamics simulations in conjunction with the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) method. We observed from our simulations that the presence of nsp10 increases the favorable van der Waals and electrostatic interactions between SAM and nsp16. Thus, nsp10 acts as a stimulator for the strong binding of SAM to nsp16. The hydrophobic interactions were predominately identified for the nsp16-nsp10 interactions. Also, the stable hydrogen bonds between Ala83 (nsp16) and Tyr96 (nsp10), and between Gln87 (nsp16) and Leu45 (nsp10) play a vital role in the dimerization of nsp16 and nsp10. Besides, Computational Alanine Scanning (CAS) mutagenesis was performed, which revealed hotspot mutants, namely I40A, V104A, and R86A for the dimer association. Hence, the dimer interface of nsp16/nsp10 could also be a potential target in retarding the 2′-O-MTase activity in SARS-CoV-2. Overall, our study provides a comprehensive understanding of the dynamic and thermodynamic process of binding nsp16 and nsp10 that will contribute to the novel design of peptide inhibitors based on nsp16.
Nisha A. Jonniya and Parimal Kar
Informa UK Limited
Abstract The With-No-Lysine (WNK) kinase family plays a significant role in regulating cation-chloride cotransporters, blood pressure and body fluid homeostasis. Mutations in the gene of WNK family, especially in WNK1 and WNK4 are responsible for pseudohypoaldosteronism type II (PHAII), characterized by hypertension. The selective inhibition of WNK1 over other isoforms has created an immense challenge in the design of an ATP competitive inhibitor due to their high conservatism. In this work, we have compared the selectivity of the inhibitor WNK463, which was designed for WNK1 with other WNK family isoforms by comprehensive molecular modeling, docking and molecular dynamics simulations in conjunction with the Molecular Mechanics Poisson-Boltzmann Surface Area method. Our calculations show that the affinity of the inhibitor decreases in the order WNK2 > WNK1 > WNK3 > WNK4, in agreement with the experiment. Our study reveals that the inhibitor is most selective to WNK2 due to decreased polar solvation and configurational entropy compared to other isoforms. Furthermore, our analyses indicated that the nonpolar contribution from the hydrophobic residues and hydrogen bonds in the hinge region gatekeeper residue Met304 of WNK1 and its equivalent residue from other kinases played a critical role in stabilizing the inhibitor against WNK kinases. Residues Lys233, Met304, Phe356 and Leu369 of WNK1 were the essential residue differences compared to other isoforms that led to specific interactions thereby forming the basis of molecular binding pattern of binding interactions. Overall, we have identified conserved WNK-inhibitor interactions and elucidated isoform-specific interactions that could be exploited in the design of more potent and selective WNK inhibitors. Communicated by Ramaswamy H. Sarma
Md Fulbabu Sk, Nisha Amarnath Jonniya, and Parimal Kar
Informa UK Limited
Abstract Non-B strains cause nearly 90% of the worldwide human immunodeficiency virus (HIV) infections. At the same time, the protease inhibitors (PIs) were designed for subtype B. Therefore, the use of PIs in the non-B subtype context requires further investigation. Herein, we have investigated the effectiveness of currently used four PIs, namely atazanavir, darunavir, lopinavir, and tipranavir against subtype CRF01_AE (PRCRF) by employing the MD/MMPBSA (molecular dynamics/molecular mechanics Poisson-Boltzmann surface area) scheme. Our investigation reveals that tipranavir is the most potent inhibitor against PRCRF while the other three PIs display a similar binding affinity. The energetic penalty arises due to the desolvation of polar groups always disfavor the association between PRCRF and PI, and this contribution is the least in the case of tipranavir/PRCRF compared to the other three PI-PRCRF complexes resulting in a better binding affinity for tipranavir. Further, it is revealed that the primary interaction controlling the binding of inhibitors with PRCRF is the van der Waals forces. The dynamic cross-correlation map and principal component analysis show that the anti-correlated motion at the flap region of PRCRF is diminished after the ligand binding. Further, our studies indicate that D25' forms a stable H-bond with darunavir, lopinavir, and tipranavir, while D25 forms a stable H-bond with atazanavir. The per-residue based decomposition of free energy reveals the actual residual origin of the binding free energy and identify the hotspot residues. Overall, the data presented in this study can guide the computer-aided rational design of more potent drugs targetting HIV-1 PRCRF. Communicated by Ramaswamy H. Sarma
Nisha Amarnath Jonniya, Md Fulbabu Sk, and Parimal Kar
American Chemical Society (ACS)
The With-No-Lysine (WNK) kinase is considered to be a master regulator for various cation-chloride cotransporters involved in maintaining cell-volume and ion homeostasis. Here, we have investigated the phosphorylation-induced structural dynamics of the WNK1 kinase bound to an inhibitor via atomistic molecular dynamics simulations. Results from our simulations show that the phosphorylation at Ser382 could stabilize the otherwise flexible activation loop (A-loop). The intrahelix salt-bridge formed between Arg264 and Glu268 in the unphosphorylated system is disengaged after the phosphorylation, and Glu268 reorients itself and forms a stable salt-bridge with Arg348. The dynamic cross-correlation analysis shows that phosphorylation diminishes anticorrelated motions and increases correlated motions between different domains. Structural network analysis reveals that the phosphorylation causes structural rearrangements and shortens the communication path between the αC-helix and catalytic loop, making the binding pocket more suitable for accommodating the ligand. Overall, we have characterized the structural changes in the WNK kinase because of phosphorylation in the A-loop, which might help in designing rational drugs.
Chaluveelaveedu Murleedharan Nisha, Ashwini Kumar, Archana Vimal, Bhukya Mounika Bai, Dharm Pal, and Awanish Kumar
Elsevier BV
Chaluveelaveedu Murleedharan Nisha, Ashwini Kumar, Prateek Nair, Nityasha Gupta, Chitrangda Silakari, Timir Tripathi, and Awanish Kumar
Hindawi Limited
Amyloidogenic pathway in Alzheimer’s disease (AD) involves breakdown of APP by β-secretase followed by γ-secretase and results in formation of amyloid beta plaque. β-secretase has been a promising target for developing novel anti-Alzheimer drugs. To test different molecules for this purpose, test ligands like acylguanidine 7a, rosiglitazone, pioglitazone, and tartaric acid were docked against our target protein β-secretase enzyme retrieved from Protein Data Bank, considering MK-8931 (phase III trial, Merck) as the positive control. Docking revealed that, with respect to their free binding energy, acylguanidine 7a has the lowest binding energy followed by MK-8931 and pioglitazone and binds significantly to β-secretase. In silico ADMET predictions revealed that except tartaric acid all other compounds had minimal toxic effects and had good absorption as well as solubility characteristics. These compounds may serve as potential lead compound for developing new anti-Alzheimer drug.