A novel approach to design chimeric multi epitope vaccine against Leishmania exploiting infected host cell proteome Sooram Banesh, Neharika Gupta, Chethireddy Vihadhar Reddy, Uppuladinne Mallikarjunachari, Nupoor Patil, Sonavane Uddhavesh, Prakash Saudagar Heliyon, 2024 Leishmaniasis is a major infectious disease having high mortality which could be attributed to lack of a suitable vaccine candidate. We propose a novel approach to design multiepitope vaccine to leishmaniasis exploiting specific membrane proteome from infected macrophage from host. The MHC-I, MHC-II and BC epitopes predicted for unique proteins from the infected macrophages and Leishmania and a MEV designed in various combinations (1a-1m). The epitope arrangements 1a, 1k, 1l, and 1m showed a strong antigenicity profile and immune response. The molecular dynamics simulation indicate the 1k, 1l, and 1m constructs have strong affinity toward TLR-2, TLR-3, and TLR-4. Overall the structural and immunogenicity profile suggests 1k is top candidate. Further, a computational model system with TLR-2, TLR-3, TLR-4, BCR, MHC-I and MHC-II was generated for 1k construct to understand the MEV interactions with immune components. Dihedral distribution and distance was enumerated to understand the movement of immune components towards 1k. The results indicate 1k has strong affinity for the immune response molecules especially TLR-3, BCR and MHC-II are coming in close contact with the MEV through the simulation. The study suggests that designed multi-epitope vaccine 1k has potential to induce proper immune response but warrants further studies. Leishmaniasis is a major infectious disease having high mortality which could be attributed to lack of a suitable vaccine candidate. We propose a novel approach to design multiepitope vaccine to leishmaniasis exploiting specific membrane proteome from infected macrophage from host. The MHC-I, MHC-II and BC epitopes predicted for unique proteins from the infected macrophages and Leishmania and a MEV designed in various combinations (1a-1m). The epitope arrangements 1a, 1k, 1l, and 1m showed a strong antigenicity profile and immune response. The molecular dynamics simulation indicate the 1k, 1l, and 1m constructs have strong affinity toward TLR-2, TLR-3, and TLR-4. Overall the structural and immunogenicity profile suggests 1k is top candidate. Further, a computational model system with TLR-2, TLR-3, TLR-4, BCR, MHC-I and MHC-II was generated for 1k construct to understand the MEV interactions with immune components. Dihedral distribution and distance was enumerated to understand the movement of immune components towards 1k. The results indicate 1k has strong affinity for the immune response molecules especially TLR-3, BCR and MHC-II are coming in close contact with the MEV through the simulation. The study suggests that designed multi-epitope vaccine 1k has potential to induce proper immune response but warrants further studies.
Pharmacophore-guided drug design using LdNMT as a model drug target for leishmaniasis Banesh Sooram, Uppuladinne Mallikarjunachari, Sonavane Uddavesh, Prakash Saudagar Journal of Biomolecular Structure and Dynamics, 2024 Leishmaniasis is caused by Leishmania genus parasites and has a high mortality rate. The available drugs to treat leishmaniasis fail due to acquired resistance in parasites. Several enzymes of the Leishmania parasite have been used to design new therapeutic molecules against leishmaniasis. This study uses a pharmacophore-guided approach to design the drug candidate by targeting Leishmania N-Myristoyl transferase (LdNMT). From the initial sequence analysis of LdNMT, we have identified a unique 20 amino acid stretch exploited for screening and designing the small molecules. The pharmacophore for the myristate binding site on LdNMT was elucidated, and a heatmap was constructed. The leishmanial NMT pharmacophore has similarities with other pathogenic microorganisms. Moreover, substituting alanine in pharmacophoric residues elevates the affinity of myristate with NMT. Furthermore, a molecular dynamics (MD) simulation study was conducted to ascertain the stability of the mutants and or wild type. The wild-type NMT has a comparatively low affinity to myristate compared to alanine mutants, indicating that hydrophobic residues favor the myristate binding. The molecules were initially designed by using pharmacophore as a sieving mechanism. In subsequent steps, the selected molecules screened against leishmanial unique amino acid stretch and subsequently with human, leishmanial full-size NMTs. The compounds BP5, TYI, DMU, 3PE and 4UL were the top hits and chemical features similar to the myristate. The molecule 4UL was found to be highly specific towards leishmanial NMT over human NMT, suggesting the molecule is a strong leishmanial NMT inhibitor. The molecule can be taken further to assess it in in-vitro conditions.
An anti-leishmanial compound 4′,7-dihydroxyflavone elicits ROS-mediated apoptosis-like death in Leishmania parasite Santanu Sasidharan, Prakash Saudagar FEBS Journal, 2023 The treatment for leishmaniasis is currently plagued by side effects such as toxicity, and the emergence of drug resistance to the available repertoire of drugs, as well as the expense of these drugs. Considering the rising concerns, we report here , the anti-leishmanial activity and mechanism of a flavone compound 4',7-dihydroxyflavone (TI 4). Four flavanoids were initially screened for anti-leishmanial activity and cytotoxicity. The results showed that the compound TI 4 exhibited higher activity and selectivity index while maintaining low cytotoxicity. Preliminary microscopic studies and FACS analysis reported that the parasite underwent apoptosis on TI 4 treatment. Further in-depth studies revealed high ROS production and thiol levels in the parasites suggesting ROS mediated apoptosis in the parasites upon TI 4 treatment. Other apoptotic indicators like intracellular Ca2+ and mitochondrial membrane potential also indicated the onset of apoptosis in the treated parasites. The mRNA expression levels signified that the redox metabolism genes were upregulated by 2-fold along with the apoptotic genes. In summary, the use of TI 4 on Leishmania parasites induces ROS-mediated apoptosis, therefore the compound has immense potential to be an anti-leishmanial drug. However, in vivo studies would be required to ascertain its safety and efficacy before we can exploit the compound against the growing leishmaniasis crisis.
Deciphering the intrinsic dynamics of unphosphorylated IRAK4 kinase bound to type I and type II inhibitors Vijayakumar Gosu, Santanu Sasidharan, Prakash Saudagar, Kamalakannan Radhakrishnan, Hak-Kyo Lee, Donghyun Shin Computers in Biology and Medicine, 2023 Interleukin-1 receptor-associated kinase 4 (IRAK4) is a vital protein involved in Toll-like and interleukin-1 receptor signal transduction. Several studies have reported regarding the crystal structure, dynamic properties, and interactions with inhibitors of the phosphorylated form of IRAK4. However, no dynamic properties of inhibitor-bound unphosphorylated IRAK4 have been previously studied. Herein, we report the intrinsic dynamics of unphosphorylated IRAK4 (uIRAK4) bound to type I and type II inhibitors. The corresponding apo and inhibitor-bound forms of uIRAK4 were subjected to three independent simulations of 500 ns (total 1.5 μs) each, and their trajectories were analyzed. The results indicated that all three systems were relatively stable, except for the type II inhibitor-bound form of uIRAK4, which exhibited less compact folding and higher solvent surface area. The intra-hydrogen bonds corroborated the structural deformation of the type-II inhibitor-bound complex, which could be attributed to the long molecular structure of the type-II inhibitor. Moreover, the type II inhibitor bound to uIRAK4 showed higher binding free energy with uIRAK4 than the type I inhibitor. The free energy landscape analysis showed a reorientation of Phe330 side chain from the DFG motif at different metastable states for all the systems. The intra-residual distance between residues Lys213, Glu233, Tyr262, and Phe330 suggests a functional interplay when the inhibitors are bound to uIRAK4, thereby hinting at their crucial role in the inhibition mechanism. Ultimately, the intrinsic dynamics study observed between type I/II inhibitor-bound forms of uIRAK4 may assist in better understanding the enzyme and designing therapeutic compounds.
Applications of infrared spectroscopy to study proteins Riya Sahu, Banesh Sooram, Santanu Sasidharan, Niharika Nag, Timir Tripathi, Prakash Saudagar Advanced Spectroscopic Methods to Study Biomolecular Structure and Dynamics, 2022
In-vitro biomineralization study of eco-friendly synthesized borosilicate glass with strontium oxide as dopant S Jain, M Monirujjaman, L Daloji, R Gujjala, PA Azeem, RK Samudrala, ... Ceramics International 51 (13), 18265-18275 , 2025 2025 Citations: 4
The landscape of intrinsically disordered proteins in Leishmania parasite: Implications for drug discovery S Gollapalli, B Sooram, H Sugandh, P Saudagar International Journal of Biological Macromolecules 283, 137290 , 2024 2024 Citations: 2
A comprehensive study on bioactivity, mechanical and tribological behavior of copper-doped borosilicate glass derived from natural waste for dental applications S Jain, R Gujjala, H Boyina, PA Azeem, RK Samudrala, P Saudagar, ... Ceramics International 50 (16), 28988-29000 , 2024 2024 Citations: 5
A novel approach to design chimeric multi epitope vaccine against Leishmania exploiting infected host cell proteome S Banesh, N Gupta, CV Reddy, U Mallikarjunachari, N Patil, S Uddhavesh, ... Heliyon 10 (10) , 2024 2024 Citations: 1
Biofunctionalized chrysin-conjugated gold nanoparticles neutralize Leishmania parasites with high efficacy (vol 205, pg 211, 2022) S Raj, S Sasidharan, T Tripathi, P Saudagar INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES 264 , 2024 2024
Corrigendum to “Biofunctionalized chrysin-conjugated gold nanoparticles neutralize Leishmania parasites with high efficacy”[Int. J. Biol. Macromol. Volume 205, 30 April 2022 … S Raj, S Sasidharan, T Tripathi, P Saudagar International Journal of Biological Macromolecules 264, 130924 , 2024 2024
Design and evaluation of a multiepitope vaccine for pancreatic cancer using immune-dominant epitopes derived from the signature proteome in expression datasets S Banesh, N Patil, VR Chethireddy, A Bhukmaria, P Saudagar Medical Oncology 41 (5), 90 , 2024 2024 Citations: 6
Pharmacophore-guided drug design using LdNMT as a model drug target for leishmaniasis B Sooram, U Mallikarjunachari, S Uddavesh, P Saudagar Journal of Biomolecular Structure and Dynamics 42 (2), 863-875 , 2024 2024 Citations: 2
4′, 7-dihydroxyflavone conjugated carbon nanotube formulation demonstrates improved efficacy against Leishmania parasite S Sasidharan, P Saudagar Biochimica et Biophysica Acta (BBA)-General Subjects 1867 (10), 130416 , 2023 2023 Citations: 5
An anti‐leishmanial compound 4′,7‐dihydroxyflavone elicits ROS‐mediated apoptosis‐like death in Leishmania parasite S Sasidharan, P Saudagar The FEBS Journal 290 (14), 3646-3663 , 2023 2023 Citations: 8
Deciphering the intrinsic dynamics of unphosphorylated IRAK4 kinase bound to type I and type II inhibitors V Gosu, S Sasidharan, P Saudagar, K Radhakrishnan, HK Lee, D Shin Computers in Biology and Medicine 160, 106978 , 2023 2023 Citations: 5
Applications of differential scanning calorimetry in studying folding and stability of proteins B Sooram, N Gupta, VR Chethireddy, T Tripathi, P Saudagar Protein Folding Dynamics and Stability: Experimental and Computational … , 2023 2023 Citations: 6
Molecular dynamics simulation to study protein conformation and ligand interaction S Sasidharan, V Gosu, T Tripathi, P Saudagar Protein folding dynamics and stability: experimental and computational … , 2023 2023 Citations: 40
pH-based molecular dynamics simulation for analysing protein structure and folding S Sasidharan, R Shukla, T Tripathi, P Saudagar Protein Folding Dynamics and Stability: Experimental and Computational … , 2023 2023 Citations: 12
Fluorescence Spectroscopy-Based Methods to Study Protein Folding Dynamics R Kumar, T Tripathi, P Saudagar Protein Folding Dynamics and Stability: Experimental and Computational … , 2023 2023 Citations: 1
Protein folding dynamics and stability: experimental and computational methods P Saudagar, T Tripathi Springer Nature , 2023 2023 Citations: 23
Discovery of compounds inhibiting SARS-COV-2 multi-targets S Sasidharan, N Sarkar, P Saudagar Journal of Biomolecular Structure and Dynamics 41 (6), 2602-2617 , 2023 2023 Citations: 6
Molecular dynamics of the ERRγ ligand-binding domain bound with agonist and inverse agonist S Sasidharan, K Radhakrishnan, JY Lee, P Saudagar, V Gosu, D Shin PLoS One 18 (4), e0283364 , 2023 2023 Citations: 18
meso-Carbazole decorated BODIPYs–an electron donor–acceptor system with excellent fluorosolvato/vapochromic behavior, aggregation-induced emission, and antileishmanial activity D Mathew, S Sasidharan, P Saudagar, S Sujatha, P Parameswaran New Journal of Chemistry 47 (17), 8277-8290 , 2023 2023 Citations: 6
Interactions and interplay of MLOs with classical membrane-bound organelles S Sasidharan, N Nag, T Tripathi, P Saudagar Droplets of Life, 375-395 , 2023 2023 Citations: 10
MOST CITED SCHOLAR PUBLICATIONS
Role of Phenols and Polyphenols in Plant Defense Response to Biotic and Abiotic Stresses P Tuladhar, S Sasidharan, P Saudagar Biocontrol Agents and Secondary Metabolites: Applications and Immunization … , 2020 2020 Citations: 246
Leishmaniasis: where are we and where are we heading? S Sasidharan, P Saudagar Parasitology research 120 (5), 1541-1554 , 2021 2021 Citations: 210
Amyloid cross-seeding: mechanism, implication, and inhibition S Subedi, S Sasidharan, N Nag, P Saudagar, T Tripathi Molecules 27 (6), 1776 , 2022 2022 Citations: 123
Biocontrol agents and secondary metabolites P Tuladhar, S Sasidharan, P Saudagar Sawston: Woodhead Publishing, 419-441 , 2021 2021 Citations: 101
High-throughput rational design of the remdesivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance AK Padhi, R Shukla, P Saudagar, T Tripathi Iscience 24 (1) , 2021 2021 Citations: 76
An overview of biochemically characterized drug targets in metabolic pathways of Leishmania parasite S Raj, S Sasidharan, SN Balaji, P Saudagar Parasitology Research 119 (7), 2025-2037 , 2020 2020 Citations: 74
Identification of lead molecules against potential drug target protein MAPK4 from L . donovani : An in-silico approach using docking, molecular dynamics and … S Raj, S Sasidharan, VK Dubey, P Saudagar PloS one 14 (8), e0221331 , 2019 2019 Citations: 71
Nanomaterial synthesis: chemical and biological route and applications S Sasidharan, S Raj, S Sonawane, S Sonawane, D Pinjari, AB Pandit, ... Nanomaterials synthesis, 27-51 , 2019 2019 Citations: 68
Molecular mechanism underlying antileishmanial effect of oxabicyclo [3.3. 1] nonanones: inhibition of key redox enzymes of the pathogen P Saudagar, P Saha, AK Saikia, VK Dubey European Journal of Pharmaceutics and Biopharmaceutics 85 (3), 569-577 , 2013 2013 Citations: 67
Miltefosine‐unresponsive Leishmania donovani has a greater ability than miltefosine‐responsive L. donovani to resist reactive oxygen species M Das, P Saudagar, S Sundar, VK Dubey The FEBS journal 280 (19), 4807-4815 , 2013 2013 Citations: 67
Cloning, expression, characterization and inhibition studies on trypanothione synthetase, a drug target enzyme, from Leishmania donovani. P Saudagar, VK Dubey Biological Chemistry 392 (12) , 2011 2011 Citations: 59
Phase separation of FG-nucleoporins in nuclear pore complexes N Nag, S Sasidharan, VN Uversky, P Saudagar, T Tripathi Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1869 (4), 119205 , 2022 2022 Citations: 57
Advanced spectroscopic methods to study biomolecular structure and dynamics P Saudagar, T Tripathi Elsevier , 2022 2022 Citations: 49
Molecular mechanisms of in vitro betulin-induced apoptosis of Leishmania donovani P Saudagar, VK Dubey The American journal of tropical medicine and hygiene 90 (2), 354 , 2014 2014 Citations: 47
Evaluation of a diospyrin derivative as antileishmanial agent and potential modulator of ornithine decarboxylase of Leishmania donovani S Hazra, S Ghosh, MD Sarma, S Sharma, M Das, P Saudagar, ... Experimental parasitology 135 (2), 407-413 , 2013 2013 Citations: 46
Review on natural products as an alternative to contemporary anti-leishmanial therapeutics S Raj, S Sasidharan, SN Balaji, VK Dubey, P Saudagar Journal of Proteins and Proteomics 11 (2), 135-158 , 2020 2020 Citations: 43
Molecular dynamics simulation to study protein conformation and ligand interaction S Sasidharan, V Gosu, T Tripathi, P Saudagar Protein folding dynamics and stability: experimental and computational … , 2023 2023 Citations: 40
Carbon nanotube based betulin formulation shows better efficacy against Leishmania parasite P Saudagar, VK Dubey Parasitology international 63 (6), 772-776 , 2014 2014 Citations: 40
Exploring the Zika genome to design a potential multiepitope vaccine using an immunoinformatics approach A Mittal, S Sasidharan, S Raj, SN Balaji, P Saudagar International Journal of Peptide Research and Therapeutics 26 (4), 2231-2240 , 2020 2020 Citations: 37
Biochemical characterization and chemical validation of Leishmania MAP Kinase-3 as a potential drug target S Raj, G Saha, S Sasidharan, VK Dubey, P Saudagar Scientific reports 9 (1), 16209 , 2019 2019 Citations: 36