Publications by authors named "Ahmad Ebadi"

23 Publications

  • Page 1 of 1

Antiproliferative effect, alteration of cancer cell cycle progression and potential MET kinase inhibition induced by 3,4-dihydropyrimidin-2(1H)-one C5 amide derivatives.

Eur J Pharmacol 2021 Mar 9;894:173850. Epub 2021 Jan 9.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Cancer continues to be the second leading cause of death worldwide. Discovery of novel therapeutic agents has crucial importance for improvement of our medical management capabilities. Dysregulation of the MET receptor tyrosine kinase pathway plays an important role in cancer progression, making this receptor an attractive molecular target for anticancer drug discovery. In this study, twenty-seven 3,4-dihydropyrimidin-2(1H)-one C5 amide derivatives were synthesized and their cancer cell growth inhibitory activity was examined against MCF-7, HT-29 and MOLT-4 cells and also NIH/3T3 non-cancer cells by MTT assay. The antiproliferative effect of the most potent derivatives were tested against MET-dependent EBC-1 and MKN-45, lung and gastric cancer cell lines, respectively. MET kinase inhibition was measured by a Homogenous Time Resolved Fluorescence (HTRF) Assay. The influence of the test compounds on cell cycle was examined by RNase/PI flow cytometric assay. A number of compounds exhibited considerable antiproliferative effects against breast and colon cancer and leukemia cell lines, relatively sparing non-cancer cells. Some derivatives bearing benzothiazolyl carboxamide moiety at C5 position (15, 21, 23, 31, and 37) showed the highest activities with IC values as low as 10.9 μM. These compounds showed antiproliferative effects also against MET-amplified cells and dose-dependently inhibited MET kinase activity. They also induced G0/G1 cell cycle arrest at lower doses and apoptosis at higher doses. Molecular docking and dynamics simulation studies confirmed the interaction of compound 23 with the active site of the MET receptor. These findings demonstrate that 3,4-dihydropyrimidin-2(1H)-one analogues may represent promising targeted anticancer agents.
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http://dx.doi.org/10.1016/j.ejphar.2021.173850DOI Listing
March 2021

Design, synthesis and biological evaluation of anticholinesterase peptides: Fragment-based vs. template-based peptide design.

Bioorg Chem 2020 12 7;105:104351. Epub 2020 Oct 7.

Department of Medicinal Chemistry, School of Pharmacy, Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran. Electronic address:

The prevalence of Alzheimer's disease (AD) has become a substantial global concern. Approved AChE inhibitors have been used for symptomatic treatment of AD. Binding of amyloid β (Aβ) to the peripheral anionic site of AChE facilitates the formation of Aβ plaques. Blocking this proposed protein-protein interaction by inhibition of the peripheral anionic site of AChE, in addition to increasing the level of ACh, reduces the Aβ aggregation and might qualify to slow down the progression of disease besides the palliative treatment. Targeting protein-protein interactions consider as one of the most challenging issues in the realm of drug design in which peptides have potentials to excel in. In the present study, we applied two virtual fragment-based and template-based approaches to design peptidic inhibitors of the PAS of AChE. Based on the in silico studies, high scored peptides p2 (WTWYGYWVW) and p10 (NHRMLTRRY) obtained from fragment-based and template-based design respectively. Regarding in vitro results, p2 (IC = 16 ± 3.2 μM) and p10 (IC = 23.6 ± 4.9 μM) showed significant AChE inhibitory effects. The molecular mechanism of inhibition studied by Lineweaver-Burk plots was mixed inhibition for both peptides. The in vitro results conformed to the in silico results and showed that both peptides occupied the CAS and PAS of AChE. The comparison of two peptide-design approaches revealed that the fragment-based design had more chemical diversity and showed priority to the template-based design. According to the obtained results, peptidic inhibitors of AChE designed by the proposed fragment-based approach might be more efficient in comparison to traditional approaches.
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http://dx.doi.org/10.1016/j.bioorg.2020.104351DOI Listing
December 2020

Identification of a potential SARS-CoV2 inhibitor via molecular dynamics simulations and amino acid decomposition analysis.

J Biomol Struct Dyn 2020 Jul 24:1-16. Epub 2020 Jul 24.

Students Research Committee, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran.

Considering lack of validated therapeutic drugs or vaccines against contagious SARS-CoV2, various efforts have been focused on repurposing of existing drugs or identifying new agents. In an attempt to identify new and potential SARS-CoV2 inhibitors targeting specific enzyme of the pathogen, a few induced fit models of SARS-CoV2 main protease (Mpro) including -aryl amide and aryl sulfonamide based fragments were subjected to a multi-step strategy. Sub-structure query of co-crystallographic fragments provided numerous ZINC15 driven commercially available compounds that entered molecular docking stage to find binding interactions/modes inside Mpro active site. Docking results were reevaluated through time dependent stability of top-ranked ligand-protease complexes by molecular dynamics (MD) simulations within 50 ns. Relative contribution of interacted residues in binding to the most probable binding pose was estimated through amino acid decomposition analysis in B3LYP level of theory with Def2-TZVPP split basis set. In confirmation of docking results, MD simulations revealed less perceptible torsional distortions (more stable binding mode) in binding of ZINC_252512772 (ΔG -9.18 kcal/mol) into Mpro active site. H-bond interactions and hydrophobic contacts were determinant forces in binding interactions of hit. Quantum chemical calculations confirmed MD results and proved the pivotal role of a conserved residue (Glu166) in making permanent hydrogen bond (98% of MD simulations time) with ZINC_252512772. Drug-like physicochemical properties as well as desirable target binding interactions nominated ZINC_252512772 as a desirable hit for further development toward SARS-CoV2 inhibitors. Highlights A few -aryl amide/aryl sulfonamide based fragments were subjected to a multi-step strategy to afford potential SARS-CoV2 Mpro inhibitors. MD simulations revealed less perceptible torsional distortions (more stable binding mode) in binding of ZINC_252512772 (ΔG -9.18 kcal/mol) into Mpro active site. H-bond interactions and hydrophobic contacts were determinant forces in binding interactions of hit. Quantum chemical calculations confirmed MD results and proved pivotal role of a conserved residue (Glu166) in making permanent hydrogen bond (98% of MD simulations time) with ZINC_252512772. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1797536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441780PMC
July 2020

To be ionized or not to be ionized: the vital role of physicochemical properties of galbanic acid derivatives in AChE assay.

J Biomol Struct Dyn 2020 May 15:1-9. Epub 2020 May 15.

Department of Pharmacognosy, School of Pharmacy, Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.

Alzheimer's disease is a progressive neurodegenerative disorder and patients suffer from memory loss, a decline in language skill and impairment in other cognitive functions. In the cholinergic hypothesis, dysfunction of cholinergic neurons especially in the hippocampus and cerebral cortex contributes to cognitive decline in patients. So agents that enhance acetylcholine concentration could improve cognitive function. AChEIs are among the most studied anti-Alzheimer agents. Galbanic acid as a natural compound with a sesquiterpene coumarin scaffold is a weak inhibitor of AChE. In the present contribution, we discussed the impact of carboxylic group ionization on inhibitory effects. We performed and studies on galbanic acid, methyl and ethyl galbanates as AChE inhibitors. The order of inhibitory effect on AChE was obtained as ethyl galbanate ∼ methyl galbanate > galbanic acid. Our study highlights the important role of the physicochemical properties of natural lead compounds in each specific assay.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1764391DOI Listing
May 2020

design of peptide inhibitors of tubulin: amyloid-β as a lead compound.

J Biomol Struct Dyn 2020 Mar 28:1-10. Epub 2020 Mar 28.

Department of Medicinal Chemistry, School of Pharmacy, Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.

Microtubule is one of the most studied targets in cancer research. Stabilizing and destabilizing of the microtubule by targeting its building block tubulin are common mechanisms of microtubule targeting agents. Cancer associates inversely with Alzheimer's disease (AD). So the rate of developing AD is significantly slower in patients with cancer and vice versa. Amyloid-β (Aβ) peptide inhibits tubulin polymerization and induces apoptotic death of cancer cells. We studied the interactions of Aβ with tubulin using protein-protein docking and MD simulation. Aβ bond to the vicinity of the vinblastine binding site and interacted with the H6-H7 loop. Interaction of Aβ with H6-H7 loop blocked nucleotide exchange and may be attributed as a possible reason for blocking of tubulin polymerization. We designed new Aβ-based peptidic inhibitors of tubulin using visual inspection and alanine scanning method. (FRHYHHFFELV) and (HYHHF) bound efficiently to tubulin and also interacted with the H6-H7 loop. Obtained results indicated that proposed peptides could potentially inhibit nucleotide exchange as Aβ.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1745691DOI Listing
March 2020

Insights into the current status of privileged N-heterocycles as antileishmanial agents.

Mol Divers 2020 May 26;24(2):525-569. Epub 2019 Apr 26.

Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, PO Box 5618953141, Ardabil, Iran.

Leishmania, one of the most important neglected tropical diseases, is endemic in several regions of the world and hence regarded as a serious threat to public health. Major difficulties with current chemotherapeutic agents raise issues such as toxicity, resistance, cost and other side effects. These issues necessitate development of potentially new chemical entities against diverse leishmanial species. Numerous natural and synthetic new antileishmanial molecules have been described for disease management. Careful inspection of scientific reports revealed that considerable amount of promising antileishmanial agents belonged to the nitrogen-containing heterocycles such as quinoline, triazole, pyrazole, imidazole, indole, pyrimidine, β-carboline, quinoxaline, quinazoline and benzimidazole. In this regard, enormous chemical data provide the opportunity for systematic elucidation of structural requirements against different leishmanial species. Within this representation, insights into the current status of privileged N-heterocycles as antileishmanial agents with particular emphasis on structure activity relationships are reviewed.
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http://dx.doi.org/10.1007/s11030-019-09953-4DOI Listing
May 2020

Molecular Modeling of Indeno [1, 2-b] Quinoline-9, 11-Diones as Cytotoxic Agents.

Iran J Pharm Res 2018 ;17(4):1249-1262

Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.

Deoxyribonucleic acid (DNA) is an important molecular target for anti-cancer agents due to its involvement in gene expression and protein synthesis which are fundamental steps in cell division and growth. A number of antineoplastic agents interfere with DNA and hence disturb the cell cycle. Compounds including planar aromatic rings are privileged scaffolds in binding to DNA. This characteristic is mainly arisen from the fact that such structural feature may be appropriate to insert between the base pairs of the DNA double helix and produce relatively stable non-covalent complexes. Besides π-π stacking interactions, binding to the DNA molecule might be intensified through H-bond interactions of heterocyclic rings. In the present contribution, a series of experimentally validated cytotoxic indeno[1,2-b]quinoline-9,11-diones (1-12) and their aromatized analogues (13-21) developed in our group were subjected to docking and molecular dynamics simulations to elucidate their most probable binding modes with DNA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269552PMC
January 2018

The potential of natural product vs neurodegenerative disorders: In silico study of artoflavanocoumarin as BACE-1 inhibitor.

Comput Biol Chem 2018 Dec 1;77:307-317. Epub 2018 Nov 1.

Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran; Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran. Electronic address:

Increasing evidence suggests the beneficial impact of flavonoid-rich nutrition on normal cognitive function. It has been revealed that flavonoids can slow neurodegenerative processes in situations such as Alzheimer's disease (AD). The β-secretase (BACE-1) is one of the most studied targets in AD therapy owing to its role in producing Aβ plaques. In fact the unique role of BACE-1 in pathogenesis of neurodegenerative diseases has made it a druggable target to develop anti-AD agents. Taking into account the anti-amyloidogenic and anti-oxidative properties, flavonoids have received considerable attention as lead candidates for anti-AD drug discovery projects. In continuation to our interest toward rational exploration of potential anti-AD agents, it was attempted to conduct a combined structure based in silico study and explore pharmacophore of a flavanocoumarin derivative as BACE-1 Inhibitor. Ab initio studies showed that both pseudo-axial and pseudo-equatorial conformers could convert to each other freely at room temperature. Within this study it was revealed that artoflavanocoumarin possess essential pharmacophoric groups to inhibit BACE-1. Considering four different protonation states of BACE-1 as di-deprotonated, diprotonated, protonated Asp32 and protonated Asp228, it was also found that affinity of artoflavanocoumarin toward different protonation states of BACE-1could be ranked as Asp32p-Asp228i > di-deprotonated ∼ Asp32i-Asp228p > diprotonated. PMF study on artoflavanocoumarin showed that it could pass 1.8 kcal/mol free energy barrier from water to DPPC lipid bilayer. Moreover the pros and cons of artoflavanocoumarin as a lead compound were elucidated.
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http://dx.doi.org/10.1016/j.compbiolchem.2018.10.015DOI Listing
December 2018

Risks of on-pump coronary artery bypass grafting surgery in patients with chronic obstructive pulmonary disease due to sulfur mustard.

Postepy Dermatol Alergol 2017 Oct 31;34(5):429-432. Epub 2017 Oct 31.

Department of Cardiac Surgery, Atherosclerosis Research Center and Imam Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Sulfur mustard (SM) is a toxic chemical agent that belongs to a class of vesicant compounds. In the 1980s it was used by the Iraqi army against Iranian forces. Sulfur mustard severely irritates the skin, eyes and lungs. The highest side effects seen in patients affected by this gas are pulmonary complications including different types of lung diseases such as bronchiolitis. It has also led to a certain type of chronic obstructive pulmonary disease called mustard lung. Similar extra-pulmonary, molecular and hormonal effects can be observed in these patients and patients with chronic obstructive pulmonary disease. Here cardiovascular complications may be one of the most dangerous visible effects. And atherosclerosis is probable following the direct effects or consequential long-term effects of SM. The development of atherosclerosis in these patients is associated with an increased risk of cardiovascular and coronary artery disease. Coronary artery bypass grafting surgery is the treatment of coronary artery disease. Doing this surgery by bypass pump has its own morbidity and due to local and systemic inflammation changes in patients with SM pulmonary disorders it may have more side effects. Therefore, detailed knowledge of inflammatory diseases as well as the serum level or even the local lung fluid of the inflammatory factors in these patients before surgery are needed so that it would be possible to reduce the rate of morbidity and mortality by normalizing the inflammatory conditions of the patients before cardiac surgery.
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http://dx.doi.org/10.5114/ada.2017.71107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831276PMC
October 2017

Investigation of the gold nanoparticles effects on the prostate dose distribution in brachytherapy: gel dosimetry and Monte Carlo method.

J Contemp Brachytherapy 2016 Oct 7;8(5):422-428. Epub 2016 Nov 7.

Department of Medical Physics, Salamat Institute, Chamran Hospital.

Purpose: In this work, gold nanoparticles (GNPs) were embedded in the MAGIC-f polymer gel irradiated with the Ir brachytherapy sources.

Material And Methods: At the first plexiglas phantom was made as the human pelvis. The GNPs were synthesized with 15 nm in diameter and 0.1 mM (0.0197 mg/ml) in concentration by using a chemical reduction method. Then, the MAGIC-f gel was synthesized. The fabricated gel was poured into the tubes located at the prostate (with and without the GNPs) locations of the phantom. The phantom was irradiated with Ir brachytherapy sources for prostate cancer. After 24 hours, the irradiated gels was read by using Siemens 1.5 Tesla MRI scanner. Following the brachytherapy practices, the absolute doses at the reference points and isodose curves were extracted and compared by experimental measurements and Monte Carlo (MC) simulations.

Results: The mean absorbed doses in the presence of the GNPs in prostate were 14% higher than the corresponding values without the GNPs in the brachytherapy. The gamma index analysis (between gel and MC) using 7%/7 mm was also applied to the data and a high pass rate achieved (91.7% and 86.4% for analysis with/without GNPs, respectively).

Conclusions: The real three-dimensional analysis shows the comparison of the dose-volume histograms measured for planning volumes and the expected one from the MC calculation. The results indicate that the polymer gel dosimetry method, which developed and used in this study, could be recommended as a reliable method for investigating the dose enhancement factor of GNPs in brachytherapy.
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http://dx.doi.org/10.5114/jcb.2016.63453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116456PMC
October 2016

Structural Insight into Binding Mode of 9-Hydroxy Aristolochic Acid, Diclofenac and Indomethacin to PLA.

Interdiscip Sci 2018 Jun 22;10(2):400-410. Epub 2016 Nov 22.

Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.

Phospholipase A (PLA) catalyzes the hydrolysis of phospholipids into arachidonic acid and lysophospholipids. Arachidonic acid is modified by cyclooxygenases into active compounds called eicosanoids that act as signaling molecules in a number of physiological processes. Excessive production of eicosanoids leads to several pathological conditions such as inflammation. In order to block the inflammatory effect of these compounds, upstream enzymes such as PLA are valid targets. In the present contribution, molecular dynamic analysis was performed to evaluate the binding of diclofenac, 9-hydroxy aristolochic acid (9-HAA) and indomethacin to PLA. Obtained results revealed that 9-HAA could form a more stable complex with PLA when compared to diclofenac and indomethacin. Furthermore, analysis of intermolecular binding energy components indicated that hydrophobic interactions were dominant in binding process. On the basis of obtained data, inhibitors bearing fused rings with hydrogen acceptor/donor substituent(s) interacted with His48 and Asp49 residues of the active site. More affinity toward PLA might be envisaged through negatively charged moieties via interaction with Trp31, Lys34 and Lys69.
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http://dx.doi.org/10.1007/s12539-016-0197-0DOI Listing
June 2018

Applications of cardiotoxicity in breast cancer: a meta-analysis.

Panminerva Med 2017 Mar 17;59(1):90-96. Epub 2016 Jun 17.

Department of Anesthesiology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Introduction: Breast cancer is the most common type of cancer in women. Many antineoplastic agents used to treat breast cancer have potentially cardiotoxic effects and may lead to chemotherapy induced cardiomyopathy and heart failure. We conducted a meta-analysis to clarify the applications of cardiotoxicity in breast cancer.

Evidence Acquisition: A published literature search was performed through PubMed, Cochrane Library, Medline, and Science Citation Index Expanded databases for articles published in English. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using random or fixed effects models. Heterogeneity was assessed using χ2 and I2 statistics. We performed a formal meta-analysis using summary measures from these studies.

Evidence Synthesis: In total, 9 published studies were included in the final analysis. The combined analysis revealed that there was non-significant regardless of the statistical ejection fraction (OR=0.98, 95% CI: 0.63-1.54, P=0.96) and left ventricular ejection fraction (OR=1.04; 95% CI: 0.69-1.56, P=0.85) decline method used. Additionally, the pooled OR was 0.99 (95% CI: 0.79-1.28) for the trastuzumab plus lapatinib combination, and 1.00 (95% CI: 0.88-1.13) for the trastuzumab plus pertuzumab combination.

Conclusions: In this meta-analysis, there was evidence indicated that there was not a significant decrease on LVEF and EF in patients who received trastuzumab plus lapatinib and trastuzumab plus pertuzumab combination. Our study suggests that the combination of two anti-HER2 agents does not significantly increase the risk for adverse compared with anti-HER2 monotherapy in patients with adequate cardiac function prior to start of therapy.
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http://dx.doi.org/10.23736/S0031-0808.16.03201-8DOI Listing
March 2017

Alternative Methods to Treat Nausea and Vomiting from Cancer Chemotherapy.

Chemother Res Pract 2015 8;2015:818759. Epub 2015 Nov 8.

Department of Toxicology, Islamic Azad University, Shahreza Branch and Medical Research Center, Jundishapur Health Development Co., Tehran, Iran.

Chemotherapy Induced Nausea and Vomiting (CINV) is among the most intensive side effects and critical concerns for patients with cancer. Most of these patients experience nausea and vomiting after chemotherapy. Sometimes, this is so annoying that it may prevent them from continuing the therapy. With the recent advances, a variety of therapeutic methods are innovated and applied to control CINV. Among them, the main methods include medicinal therapy, relaxation, and herbal therapy. Yet, using dexamethasone together with massage therapy and ginger is identified as the most effective method.
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http://dx.doi.org/10.1155/2015/818759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655029PMC
December 2015

Effect of Biomolecular Conformation on Docking Simulation: A Case Study on a Potent HIV-1 Protease Inhibitor.

Iran J Pharm Res 2015 ;14(3):785-802

Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran.

Human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) is a disease pertained to the human immune system. Given its crucial role in viral replication, HIV-1 protease (HIV-1 PR) is a prime therapeutic target in AIDS therapy. In this regard, the dynamic aspects of ligand-enzyme interactions may indicate an important role of conformational variability in HIV-1 PR inhibitor/drug design. In the present contribution, the effect of HIV-1 PR flexibility (within multiple crystallographic structures of HIV-1 PR) on binding to the Amprenavir was elucidated via an ensemble docking approach. Molecular docking studies were performed via advanced AutoDock4.2 software. Ensemble docking of Amprenavir into the active site of various conformations of HIV-1 PR predicted different interaction modes/energies. Analysis of binding factors in terms of docking false negatives/positives revealed a determinant role of enzyme conformational variation in prediction of optimum induced fit (PDB ID: 1HPV). The outcomes of this study demonstrated that conformation of receptor may significantly affect the accuracy of docking/binding results in structure-based rational design of anti HIV-1 PR agents. Furthermore; some strategies to re-score the docking results in HIV-1 PR targeted docking studies were proposed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518107PMC
September 2015

A Validation Study for POSSUM and EuroSCORE as a Predictor of Mortality After Selective Cardiac Surgery.

Acta Med Indones 2015 Jan;47(1):38-44

Naft Grand Hospital, The health Affaire Organization of Oils and Refineries Industry, Ahvaz, Iran.

Aim: to assess physiological and operative severity score for the enumeration of mortality (POSSUM) scoring system and compare it with European system for cardiac operative risk evaluation (EuroSCORE) scores in patients who underwent cardiac surgery from two hospitals in the southwestern region of Iran.

Methods: in this retrospective study, total of all 1420 patients who were admitted for elective cardiac surgery at our centers, from 2007 to 2012, were scored using the POSSUM and EuroSCORE systems.

Results: the overall mortality rate was 0.87%. Among the risk factors, history of diabetes, smoking, respiratory disease, and myocardial infarction, were significantly affect the mortality rate. Therefore, of these risk factors, only the hemoglobin was significantly correlated with the morbidity rate. The predictive accuracy of mortality equations was 74.5%. The lower predictive accuracy of mortality equations was 67.8% was observed using EuroSCORE.

Conclusion: although results are statistically significant, but the analysis have never intended to affect the decision to operate, and this decision must be based on clinical expertise, because of the need to standardize data collection and stratify the risks involved in operations, scoring systems such as POSSUM should be used prospectively. However, if analyzed correctly, POSSUM is a good predictor of mortality in patients undergoing cardiac surgery.
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January 2015

Cardiac Surgery Anesthesia And Systemic Inflammatory Response.

Int J Bioassays 2015 ;4(2):3648-3655

Toxicologist, Departments of Toxicology, Shahreza Branch, Islamic Azad University, Shahreza, Iran and Medical Research Center, Jundishapur Health Development Co, Tehran, Iran.

Cardiac surgery is associated with the development of a systemic inflammatory response. Inflammation represents the response of the body to tissue injury and in normal circumstances is a controlled humoral and cellular response that will lead to control of infection and wound healing. In some instances this response may become exaggerated, ultimately leading to additional tissue injury and the development of organ dysfunction. In this paper we discuss about relationships between cardiac surgery anesthesia and systemic inflammatory response.
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http://dx.doi.org/10.21746/ijbio.2015.02.005DOI Listing
January 2015

Ab-initio and Conformational Analysis of a Potent VEGFR-2 Inhibitor: A Case Study on Motesanib.

Iran J Pharm Res 2014 ;13(2):405-15

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. ; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran .

Vascular endothelial growth factor receptor-2 (VEGFR-2); a cell surface receptor for vascular endothelial growth factors, is a key pharmacological target involved in the cell proliferation/angiogenesis. It has been revealed that VEGFR-2 induces proliferation through activation of the extracellular signal-regulated kinases pathway. In this regard, targeting the VEGFR-2 has been considered as an efficient route to develop anti-tumor agents. Motesanib is a small-molecule antagonist of VEGFR-1, 2, and 3 (IC50s; 2 nM, 3 nM, 6 nM, respectively). It is an experimental drug candidate undergoing clinical trials against some types of cancer. In the present study, Motesanib (AMG 706) was evaluated in terms of its binding energies with individual amino acids of VEGFR-2 active site (amino acid decomposition analysis). For this purpose, functional B3LYP associated with split valence basis set using polarization functions (Def2-SVP) was used. Comparative conformational analysis of the ligand in optimized and crystallographic states revealed that Motesanib does not necessarily bind to the VEGFR-2 active site in its minimum energy conformer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157016PMC
September 2014

Analgesic effect of low dose subcutaneous ketamine administration before and after cesarean section.

Iran Red Crescent Med J 2014 Mar 5;16(3):e15506. Epub 2014 Mar 5.

Pain Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran ; Department of Anesthesiology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran.

Background: Pain is considered as an importantissue after cesarean section. Multimodal approach to post cesarean pain management may not only enhance analgesia but also reduce side effects after the surgery.

Objectives: This study was aimed to evaluate the clinical efficacy of subcutaneous injection of low dose ketamine at the incision site to reduce cesarean section pain.

Patients And Methods: Sixty patients, aged between 18 and 25 years old, scheduled for elective cesarean section, were enrolled to this double-blind randomized controlled trial study. Patients were divided into three groups of 20 patients each group one (k-pre) received 0.5 mg/kg ketamine before skin incision and normal saline after skin closure, group two (k-post) received normal saline before skin incision and 0.5 mg/kg ketamine after skin closure and group three (C) received normal saline before skin incision and after skin closure; subcutaneously at the incision site. The first analgesic request, the amount of analgesic and the pain intensity were evaluated for 24 hours.

Results: The first time analgesic requested was longer and the amount of analgesic used during the first 24 hours was significantly lower in groups K-pre and K-post compared with group C (P < 0.05). Pain intensity was significantly lower at 2, 4, 6 and 12 hours in groups K-pre and K-post compared with group C (P < 0.05). Nevertheless, pain intensity was not significantly different at 18 and 24 hours in group C (P > 0.05). The first requested time, total used amount of analgesicand pain intensity were not meaningfully different in K-pre and K-post groups (P > 0.05).

Conclusions: Patients who were given ketamine before or after cesarean section subcutaneously at incision site had lower pain intensity and less analgesic consumption than patients who were given placebo.
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http://dx.doi.org/10.5812/ircmj.15506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005445PMC
March 2014

Ankylosing spondylitis in a military aviator: air medical considerations.

Air Med J 2014 May-Jun;33(3):115-7

Aerospace Medicine Research Center, Aerospace and Subaquatic Medicine School, AJA University of Medical Sciences, Tehran, Iran.

Rheumatologic diseases are a challenging diagnosis when it comes to air medical disposition decision making because many of these diseases overlap and their initial presentation is insidious and relapsing remitting in future scope. Many rheumatologic diseases have musculoskeletal and other organ complications. One of these diagnoses is spondyloarthritides. These disorders include ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis and spondylitis, enteropathic arthritis and spondylitis, juvenile-onset spondyloarthritis, and undifferentiated spondyloarthritis. The prevalence of spondyloarthropathy is estimated to be between 0.1% and 2.5%,(1) although figures vary from 1 study to another. In this article, we report the case of a military pilot diagnosed with AS who had a favorable response to treatment with etanercept therapy.
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http://dx.doi.org/10.1016/j.amj.2014.01.004DOI Listing
August 2015

Fragment-based Binding Efficiency Indices in Bioactive Molecular Design: A Computational Approach to BACE-1 Inhibitors.

Iran J Pharm Res 2013 ;12(3):423-36

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran, PO Box 3288-71345. ; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran, PO Box 1583-71345.

One of the most important targets in Alzheimer disease is Beta site amyloid precursor protein cleaving enzyme-1 (BACE-1). It is a membrane associated protein and is one of the main enzymes responsible for amyloid β (Aβ) production. Up to now, a considerable number of peptidic and non-peptidic inhibitors of BACE-1 have been developed. Recently, small molecule BACE-1 inhibitors have attracted the attention of scientists, because peptidic inhibitors have many pharmacokinetic problems. In the present study, several small molecule BACE-1 inhibitors were extracted from Brookhaven Protein Databank (PDB) and subjected to dissection analysis to achieve constructing fragments. Atom type, hybridization, and bond order were considered for generated constitutional fragments (simplified structures). AutoDock version 4.2 was applied to dock various chemical fragments into BACE-1 active site. The benefits of such studies have been well revealed in previous reports. On the basis of obtained binding affinities, fragment-based ligand efficiency (LE) indices were estimated. These theoretical binding efficiencies were applied to further elucidate the key structural features of BACE-1 inhibitors. Typical results of the study were elucidated and we suggested the ways these findings might be beneficial to guide rational bioactive molecular developments. Our study confirmed that the evaluation of ligand-receptor interactions in terms of ligand efficiency indices (binding energy per atom and pKi per MW) could be a helpful strategy in structure-based drug discovery (SBDD) strategies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813291PMC
November 2013

Is presence of bacteria in preoperative microscopic urinalysis of the patients scheduled for cardiac surgery a reason for cancellation of elective operation?

Anesth Pain Med 2013 26;2(4):174-7. Epub 2013 Mar 26.

Department of Anesthesiology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Background: In some hospitals, urinalysis is done routinely for all patients scheduled for cardiac surgery. Occasionally pyuria or bacteria is reported in the microscopic urinalysis of these patients that are clinically asymptomatic for urinary tract infections.

Objectives: WE WERE SEEKING ANSWER TO THIS QUESTION: is the presence of a different number of bacteria in preoperative microscopic urinalysis of asymptomatic patients scheduled for cardiac surgery indicative of potential postoperative complications and as a result, a good reason to postpone the operation?

Patients And Methods: We conducted a retrospective cross-sectional study based on the review of the medical records of 1165 patients who underwent open-heart surgery.

Results: One hundered and fifty one patients were eligible in our established criteria. There were no significant difference between their demographic characteristics and the same number of randomly selected patients with normal urinalysis who had underwent open-heart surgery. In the bacteriuria group, two patients, and in the control group, three patients had an infection at the operation sites in the post-operative period, which was not a significant finding between two groups (P = 0.503).

Conclusions: We recommend that in the absence of symptoms of urinary tract infection, urinalysis is not necessary and not cost beneficial in the preoperative evaluation of patients scheduled for open-heart surgery.
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http://dx.doi.org/10.5812/aapm.8667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821143PMC
November 2013

Comparative amino acid decomposition analysis of potent type I p38α inhibitors.

Daru 2013 May 29;21(1):41. Epub 2013 May 29.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, PO Box 3288-71345, Shiraz, Iran.

Background And Purpose Of The Study: p38α is a member of mitogen-activated protein kinases (MAPK) considered as a prominent target in development of anti-inflammatory agents. Any abnormality in the phosphorylation process leads to the different human diseases such as cancer, diabetes and inflammatory diseases. Several small molecule p38α inhibitors have been developed up to now. In this regard, structural elucidation of p38 inhibitors needs to be done enabling us in rational lead development strategies.

Methods: Various interactions of three potent inhibitors with p38α active site have been evaluated in terms of binding energies and bond lengths via density function theory and MD simulations.

Results: Our comparative study showed that both ab initio and MD simulation led to the relatively similar results in pharmacophore discrimination of p38α inhibitors.

Conclusion: The results of the present study may find their usefulness in pharmacophore based modification of p38α inhibitors.
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http://dx.doi.org/10.1186/2008-2231-21-41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680208PMC
May 2013

Response surface methodology in docking study of small molecule BACE-1 inhibitors.

J Mol Model 2012 Oct 13;18(10):4567-76. Epub 2012 May 13.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, PO Box 3288-71345, Shiraz, Iran.

Computational evaluation of ligand-receptor binding via docking strategy is a well established approach in structure-based drug design. This technique has been applied frequently in developing molecules of biological interest. However, any procedure would require an optimization set up to be more efficient, economic and time-saving. Advantages of modern statistical optimization methods over conventional one-factor-at-a-time studies have been well revealed. The optimization by experimental design provides a combination of factor levels simultaneously satisfying the requirements considered for each of the responses and factors. In this study, response surface method was applied to optimize the prominent factors (number of genetic algorithm runs, population size, maximum number of evaluations, torsion degrees for ligand and number of rotatable bonds in ligand) in AutoDock4.2-based binding study of small molecule β-secretase inhibitors as anti-alzheimer agents. Results revealed that a number of rotatable bonds in ligand and maximum number of docking evaluations were determinant variables affecting docking outputs. The interference between torsion degrees for ligand and number of genetic algorithm runs for docking procedure was found to be the significant interaction term in our model. Optimized docking outputs exhibited a high correlation with experimental fluorescence resonance energy transfer-based IC₅₀s for β-secretase inhibitors (R² = 0.9133).
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http://dx.doi.org/10.1007/s00894-012-1424-1DOI Listing
October 2012