Dr Madhu Sudhana Saddala, PhD - University of Missouri School of Medicine - Postdoctoral Fellow

Dr Madhu Sudhana Saddala

PhD

University of Missouri School of Medicine

Postdoctoral Fellow

Columbia, Missouri | United States

Additional Specialties: Bioinformatics

ORCID logohttps://orcid.org/0000-0002-6373-7080


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Dr Madhu Sudhana Saddala, PhD - University of Missouri School of Medicine - Postdoctoral Fellow

Dr Madhu Sudhana Saddala

PhD

Introduction

Primary Affiliation: University of Missouri School of Medicine - Columbia, Missouri , United States

Additional Specialties:

Research Interests:

Education

Jul 2016
Sri Venkateswara University
PhD
Bioinformatics
Apr 2008
Sri Venkateswara University
MSc
Bioinformatics
Apr 2005
Sri Venkateswara University
BSc
Biotechnology
Apr 2001
KPR Junior College
XII
BiPC

Experience

Nov 2018
University of Missouri
Post_Doctoral Research Associate
Ophthalmology
Nov 2017 - Oct 2018
Johns Hopkins University
Post_Doctoral Research Associate
Ophthalmology
Jun 2017
Research Associate
RA
NGS Data analysis
Feb 2016
Senior Research Fellow
SRF
Bioinformatics
May 2013
APSET
Lecturership
Life Science
Feb 2013
Junior Research Fellow
JRF
Bioinformatics
Dec 2011
CSIR-NET
Lecturership
Life Science

Publications

10Publications

207Reads

2Profile Views

27PubMed Central Citations

Autoimmune-Mediated Retinopathy in CXCR5-Deficient Mice as the Result of Age-Related Macular Degeneration Associated Proteins Accumulation.

Front Immunol 2019 14;10:1903. Epub 2019 Aug 14.

Department of Ophthalmology, University of Missouri, Columbia, MO, United States.

Previous research has shown that CXCR5 mice develop retinal degeneration (RD) with age, a characteristic related to age macular degeneration (AMD). RD in these mice is not well-understood, and in this study, we sought to characterize further the RD phenotype and to gain mechanistic insights into the function of CXCR5 in the retina. CXCR5 and WT control mice were used. Fundus images demonstrated a significant ( < 0.001) increase of hypo-pigmented spots in the retina of aged CXCR5 mice compared with WT control mice. PAS staining indicated localization of deposits in the sub-retinal pigment epithelia (RPE) layer. AMD-associated proteins Cryab, amyloid beta, and C3d were detected within the RPE/sub-RPE tissues by immunofluorescence (IF). In addition, western blot analysis of COX-2, Arg1, and VEGF-a revealed an increase in the signaling of these molecules within the RPE/choroid complex. Transmission electron microscopy (TEM) indicated a drusen-like structure of sub-RPE deposits with an accumulation of vacuolated cellular debris. Loss of photoreceptors was detected by peanut lectin staining and was corroborated by a reduction in MAP2 signaling. Loss of blood-retinal barrier integrity was demonstrated by a reduction of ZO-1 expression. Inflammatory cells were detected in the sub-RPE space, with an increase in IBA-1 positive microglia cells on the surface of the RPE. Mass spectrometry analysis of CXCR5 mouse RPE/choroid proteins extracts, separated by SDS-page and incubated with autologous serum, identified autoantibodies against AMD-associated proteins: Cryaa, Cryab, and Anxa2. evaluations in BV-2 cell culture indicated a significant increase in production of Arg-1 ( < 0.001) and COX-2 ( < 0.01) in the presence of anti-CXCR5 antibody when compared with Igg-treated control BV-2 cells stimulated with IL-4 and TNF?/IFN?, respectively. Anti-CXCR5 antibody treatment without stimulating agents did not affect Arg-1 and COX-2 expression; this suggests that CXCR5 may have a regulatory role in microglia cells activation. These results indicate that with age, CXCR5 mice develop RD characterized by microglia dysfunction, increased production of CXCL13 in the RPE progressive photoreceptor, neuronal loss, and sub-RPE deposition of cellular debris, resulting in the production of immunogenic proteins and autoimmune-mediated RD.

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http://dx.doi.org/10.3389/fimmu.2019.01903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702970PMC
August 2019
2 Reads
4.700 Impact Factor

Identification of novel inhibitors for TNFα, TNFR1 and TNFα-TNFR1 complex using pharmacophore-based approaches.

J Transl Med 2019 Jul 2;17(1):215. Epub 2019 Jul 2.

School of Medicine, Dept. Ophthalmology, Mason Eye Institute, University of Missouri, One Hospital Drive, MA102C, Columbia, MO, 65212, USA.

Background: Tumor necrosis factor ? (TNF?) is a multifunctional cytokine with a potent pro-inflammatory effect. It is a validated therapeutic target molecule for several disorders related to autoimmunity and inflammation. TNF?-TNF receptor-1 (TNFR1) signaling contributes to the pathological processes of these disorders. The current study is focused on finding novel small molecules that can directly bind to TNF? and/or TNFR1, preventing the interaction between TNF? or TNFR1, and regulating downstream signaling pathways.

Methods: Cheminformatics pipeline (pharmacophore modeling, virtual screening, molecular docking and in silico ADMET analysis) was used to screen for novel TNF? and TNFR1 inhibitors in the Zinc database. The pharmacophore-based models were generated to screen for the best drug like compounds in the Zinc database.

Results: The 39, 37 and 45 best hit molecules were mapped with the core pharmacophore features of TNF?, TNFR1, and the TNF?-TNFR1 complex respectively. They were further evaluated by molecular docking, protein-ligand interactions and in silico ADMET studies. The molecular docking analysis revealed the binding energies of TNF?, TNFR1 and the TNF?-TNFR1 complex, the basis of which was used to select the top five best binding energy compounds. Furthermore, in silico ADMET studies clearly revealed that all 15 compounds (ZINC09609430, ZINC49467549, ZINC13113075, ZINC39907639, ZINC25251930, ZINC02968981, ZINC09544246, ZINC58047088, ZINC72021182, ZINC08704414, ZINC05462670, ZINC35681945, ZINC23553920, ZINC05328058, and ZINC17206695) satisfied the Lipinski rule of five and had no toxicity.

Conclusions: The new selective TNF?, TNFR1 and TNF?-TNFR1 complex inhibitors can serve as anti-inflammatory agents and are promising candidates for further research.

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http://dx.doi.org/10.1186/s12967-019-1965-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604280PMC
July 2019
1 Read
4.010 Impact Factor

Small molecule tyrosine kinase inhibitors and pancreatic cancer-Trials and troubles.

Semin Cancer Biol 2019 Jun 9;56:149-167. Epub 2018 Oct 9.

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA-30322, USA. Electronic address:

Pancreatic cancer (PC) is an aggressive carcinoma and the fourth cause of cancer deaths in Western countries. Although surgery is the most effective therapeutic option for PC, the management of unresectable, locally advanced disease is highly challenging. Our improved understanding of pancreatic tumor biology and associated pathways has led to the development of various treatment modalities that can control the metastatic spread of PC. This review intends to present trials of small molecule tyrosine kinase inhibitors (TKIs) in PC management and the troubles encountered due to inevitable acquired resistance to TKIs.

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http://dx.doi.org/10.1016/j.semcancer.2018.09.011DOI Listing
June 2019
10 Reads
1 Citation
10.100 Impact Factor

Molecular docking studies of angiogenesis target protein HIF-1α and genistein in breast cancer.

Gene 2019 Jun 28;701:169-172. Epub 2019 Mar 28.

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta GA-30322, USA. Electronic address:

Therapeutic inhibition of hypoxia inducible factor-1? (HIF-1?) action has emerged as a potential approach for managing several diseases including breast cancer (BC). Genistein has been found to exert anti-malignant activity. However, its mechanisms of action remain unknown. Studies indicate that it could act by downregulating HIF-1?. Based on these findings, we investigated whether genistein could reduce HIF-1? in BC cell lines. Furthermore, we performed molecular docking studies to characterize the sites of interaction between genistein and HIF-1?. In the present investigation, we prove, for the first time, that genistein downregulates HIF-1? in BC cells. Molecular docking analysis also revealed that genistein binds to the FIH-1 binding site of HIF-1? protein. These findings thus indicate that genistein and/or HIF-1? antagonists could be a potential treatment for BC.

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http://dx.doi.org/10.1016/j.gene.2019.03.062DOI Listing
June 2019
2 Reads
1 Citation
2.600 Impact Factor

Transcriptome-wide analysis of differentially expressed chemokine receptors, SNPs, and SSRs in the age-related macular degeneration.

Hum Genomics 2019 03 20;13(1):15. Epub 2019 Mar 20.

Mason Eye Institute, University of Missouri, Columbia, MO, 65212, USA.

Background: Age-related macular degeneration (AMD) is the most common, progressive, and polygenic cause of irreversible visual impairment in the world. The molecular pathogenesis of the primary events of AMD is poorly understood. We have investigated a transcriptome-wide analysis of differential gene expression, single-nucleotide polymorphisms (SNPs), indels, and simple sequence repeats (SSRs) in datasets of the human peripheral retina and RPE-choroid-sclera control and AMD.

Methods And Results: Adaptors and unbiased components were removed and checked to ensure the quality of the data sets. Molecular function, biological process, cellular component, and pathway analyses were performed on differentially expressed genes. Analysis of the gene expression datasets identified 5011 upregulated genes, 11,800 downregulated genes, 42,016 SNPs, 1141 indels, and 6668 SRRs between healthy controls and AMD donor material. Enrichment categories for gene ontology included chemokine activity, cytokine activity, cytokine receptor binding, immune system process, and signal transduction respectively. A functional pathways analysis identified that chemokine receptors bind chemokines, complement cascade genes, and create cytokine signaling in immune system pathway genes (p value
Conclusions: Our results improve our overall understanding of the chemokine receptors' signaling pathway in AMD conditions, which may lead to potential new diagnostic and therapeutic targets.

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http://dx.doi.org/10.1186/s40246-019-0199-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425613PMC
March 2019
3 Reads
1 Citation
3.500 Impact Factor

Proteomics reveals ablation of PlGF increases antioxidant and neuroprotective proteins in the diabetic mouse retina.

Sci Rep 2018 Nov 13;8(1):16728. Epub 2018 Nov 13.

Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.

Placental growth factor (PlGF or PGF), a member of the vascular endothelial growth factor (VEGF) sub-family, plays a crucial role in pathological angiogenesis and inflammation. However, the underlying molecular mechanisms that PlGF mediates regarding the complications of non-proliferative diabetic retinopathy (DR) remain elusive. Using an LC-MS/MS-based label-free quantification proteomic approach we characterized the alterations in protein expression caused by PlGF ablation in the retinas obtained from C57BL6, Akita, PlGF and Akita.PlGF mice. After extraction and enzymatic digestion with Trypsin/LysC, the retinal proteins were analyzed by Q-Exactive hybrid Quadrupole-Orbitrap mass spectrometry. Differentially expressed proteins (DEPs) were identified in four comparisons based on Z-score normalization and reproducibility by Pearson's correlation coefficient. The gene ontology (GO), functional pathways, and protein-protein network interaction analysis suggested that several proteins involved in insulin resistance pathways (Gnb1, Gnb2, Gnb4, Gnai2, Gnao1, Snap2, and Gngt1) were significantly down-regulated in PlGF ablated Akita diabetic mice (Akita.PlGF vs. Akita) but up-regulated in Akita vs. C57 and PlGF vs. C57 conditions. Two proteins involved in the antioxidant activity and neural protection pathways, Prdx6 and Map2 respectively, were up-regulated in the Akita.PlGF vs. Akita condition. Overall, we predict that down-regulation of proteins essential for insulin resistance, together with the up-regulation of antioxidant and neuroprotection proteins highlight and epitomize the potential mechanisms important for future anti-PlGF therapies in the treatment of DR.

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http://www.nature.com/articles/s41598-018-34955-x
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http://dx.doi.org/10.1038/s41598-018-34955-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233167PMC
November 2018
137 Reads
3 Citations
5.078 Impact Factor

Discovery of small molecules through pharmacophore modeling, docking and molecular dynamics simulation against Vivapain-3 (VP-3).

Heliyon 2018 May 8;4(5):e00612. Epub 2018 May 8.

Sri Venkateswara University, Tirupati, 517502, Andhra Pradesh, India.

Vivapain-3(VP-3) protein is a family of cysteine rich proteases of malaria parasite is extensively reported to participate in a range of wide cellular processes including survival. VP-3 of plasmodium recognized as an attractive drug target in vector-borne diseases like malaria. In the present study we robust a homology model of VP-3 protein and generated the pharmacophore based models adapted to screen the best drug like compounds from PubChem database. Our results finds the fourteen best lead molecules were mapped with core pharmacophore features of VP-3 and top hits were further evaluated by molecular dynamics simulation and docking studies. Based on the molecular dynamics simulation and docking results and binding vicinity of ligand molecules, top five i.e., CID 74427945, CID 74427946, CID 360883, CID193721 and CID 51416859 showed the best docking scores with good molecular interactions against VP-3. Furthermore ADMET and assays clearly exhibited that out of five three CID74427946, CID74427945 and CID360883 ligand molecules showed the best promising inhibition against VP-3. The present study believed to provide significant information of potential ligand inhibitors against VP-3 to design and develop the next generation malaria therapeutics through computational approach.

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http://dx.doi.org/10.1016/j.heliyon.2018.e00612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944417PMC
May 2018
17 Reads

Molecular docking based screening of a simulated HIF-1 protein model for potential inhibitors.

Bioinformation 2017 30;13(11):388-393. Epub 2017 Nov 30.

Centre for agricultural Bioinformatics, ICAR-IASRI (Indian Agricultural Statistics Research Institute), Library Avenue, Pusa, New Delhi - 110012, India.

Hypoxia inducible factor-1(HIF-1) is a bHLH-family transcription factor that control genes involved in glucolysis, angiogenesis, migration, as well as invasion factors that are important for tumor progression and metastasis. HIF-1, a hetero dimer of HIF-1? and HIF-1?, binds to the hypoxia responsive genes, such as vascular endothelial growth factor (VEGF). It is one the molecular target for angiogenesis. A series of Chalcone - like compounds described that preferentially inhibit HIF-1 dimer, which can interact with amino acids within the active site of the protein. It is of interest model the HIF-1 dimer protein and protein was subjected to molecular dynamics simulations using NAMD 2.9 software with CHARMM27 force field in water and the protein structure was minimized with 25000 steps for 500 ps and simulation with 1000000 steps for 2ns. 2500 compounds were screened from Zinc database through structure based virtual screening with references to Chalcone natural drug compound. The screened compounds were docked into the active site of the protein using AutoDock Vina in PyRx Virtual screening tool. The docking result showed the compounds Zinc04280532, Zinc04280533, Zinc04280469, Zinc04280534, Zinc16405915, Zinc04277060, Zinc04280538, Zinc04582923, Zinc05280554 and Zinc05943723 have high binding affinities then query compound. The lead hit compounds were also testing for toxicity and bioavailability using Osiris and Molinspiration online server. The active site amino acids such as TYR-21, ASN-34, VAL-35, MET-18, LYS-17, SER-36, ARG- 46 and ARG-14 are key role in the inhibitors activity. This is useful in the design of small molecule therapeutics or the treatment of different abnormalities associated with impaired HIF-1?.

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http://dx.doi.org/10.6026/97320630013388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712784PMC
November 2017
17 Reads
9 Citations
0.850 Impact Factor

Sulfonamides and carbamates of 3-fluoro-4- morpholinoaniline (linezolid intermediate): synthesis, antimicrobial activity and molecular docking study

4

Research Chemical Intermediates

The precursor compound 3-fluoro-4-morpholinoaniline (7) is an important intermediate of the antibiotic drug linezolid and was synthesized initially by the substitution of morpholine (5) on 1,2-difluoro-4-nitrobenzene (4) under neat conditions, resulting in 4-(2-fluoro-4-nitrophenyl)morpholine (6) followed by its nitro group reduction with Fe/NH4Cl. A series of new sulfonamides (9a–e) and carbamates (11a–e) have been synthesized in good yields (75–89%) by the reaction of substituted aryl sulfonyl chlorides (8a–e) and substituted aryl/acyclic chloroformates (10a–e) with precursor compound 7, respectively, for biological interest. Structures of the title products were elucidated by spectroscopic data such as IR, NMR (1H and 13C NMR) and mass and elemental analyses. The antimicrobial potency of title products was examined by the screening of growth of zone of inhibition against four bacteria and four fungi, and minimum inhibitory concentration (MIC) was also determined. Most of the compounds showed good to potent antimicrobial activity, whereas the title products, 9d and 9e against bacterial strains, and 9a, 9b, 9d and 11a against fungi, exhibited promising activity in the MIC range of 6.25–25.0 lg/mL. The whole biological activity results revealed that the sulfonamide derivatives behaved as potent antifungal agents as compared to the carbamate derivatives. Molecular docking studies of the crystal structure of topoisomerase II gyrase A complexed with natural inhibitor, clorobiocin (1kzn), using the molecular operating environment (MOE) programme were performed in order to predict the affinity and orientation of the synthesized compounds at the active enzyme site. The test compounds showed good binding affinities and formed hydrogen bonds with a surrounding of amino acids at the active sight, whereas compounds 9d (-189.0 kcal/mol) and 11a (-280.3 kcal/mol) exhibited high binding affinities and good agreement with in vitro antimicrobial screening.

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September 2017

4 Citations

Impact Factor 2.200

6 Reads

Novel 1, 4-dihydropyridines for L-type calcium channel as antagonists for cadmium toxicity.

Sci Rep 2017 03 27;7:45211. Epub 2017 Mar 27.

Division of Bioinformatics, Department of Zoology, Sri Venkateswara University, Tirupati, 517502, A.P., India.

The present study, we design and synthesize the novel dihydropyridine derivatives, i.e., 3 (a-e) and 5 (a-e) and evaluated, anticonvulsant activity. Initially due to the lacuna of LCC, we modeled the protein through modeller 9.15v and evaluated through servers. Docking studies were performed with the synthesized compounds and resulted two best compounds, i.e., 5a, 5e showed the best binding energies. The activity of intracellular Ca measurements was performed on two cell lines: A7r5 (rat aortic smooth muscle cells) and SH-SY5Y (human neuroblastoma cells). The 5a and 5e compounds was showing the more specific activity on L-type calcium channels, i.e. A7r5 (IC?=?0.18?±?0.02 and 0.25?±?0.63??g/ml, respectively) (containing only L-type channels) than SH-SY5Y (i.e. both L-type and T-type channels) (IC?=?8?±?0.23 and 10?±?0.18??g/ml, respectively) with intracellular calcium mobility similar to amlodipine. Finally, both in silico and in vitro results exploring two derivatives 5a and 5e succeeded to treat cadmium toxicity.

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http://dx.doi.org/10.1038/srep45211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366925PMC
March 2017
18 Reads
8 Citations
5.078 Impact Factor

Top co-authors

Hu Huang
Hu Huang

Wilmer Eye Institute

4
Anton Lennikov
Anton Lennikov

Linkoping University, Far Eastern Federal University

3
Pradeepkiran Jangampalli Adi
Pradeepkiran Jangampalli Adi

Internal medicine/Texas Tech Health Sciences Center

2
Ganji Purnachandra Nagaraju
Ganji Purnachandra Nagaraju

Winship Cancer Institute

2
Shibo Tang
Shibo Tang

Sun Yat-sen University

2
Anthony Mukwaya
Anthony Mukwaya

Institute for Clinical and Experimental Medicine

2
Nagendra Sastry Yarla
Nagendra Sastry Yarla

GITAM University

1
Pallaval Veera Bramhachari
Pallaval Veera Bramhachari

Krishna University

1
Mohammad Amjad Kamal
Mohammad Amjad Kamal

King Fahd Medical Research Center

1