Ramin Ekhteiari Salmas

King's College London | KCL · Department of Chemistry

Observed mass shifts associated with deuterium incorporation in hydrogen−deuterium exchange mass spectrometry (HDX-MS) frequently deviate from the initial signals due to back and forward exchange. In typical HDX-MS experiments, the impact of these disparities on data interpretation is generally low because relative and not absolute mass changes are...

An original approach that adopts machine learning inference to predict protein structural information using hydrogen–deuterium exchange mass spectrometry (HDX-MS) is described. The method exploits an in-house optimization program that increases the resolution of HDX-MS data from peptides to amino acids. A system is trained using Gradient Tree Boost...

Background: Cholinesterase (ChE) inhibitors used currently in clinics for the treatment of Alzheimer’s disease (AD) are the most prescribed drug class with nitrogen-containing chemical formula. Galanthamine, the latest generation anti-ChE drug, contains an isoquinoline structure Objective: The aim of the current study was to investigate the inhibi...

The EtOH extracts of the leaves of two new cultivars (Uysal-SFU and Turgut-SFT) of Salvia fruticosa Mill. was tested against acetylcholinesterase (IC50: 30.62 ± 3.27 and 32.97 ± 2.33 µg/mL for SFU and SFT, respectively) and butyrylcholinesterase (IC50: 69.91 ± 1.08 µg/mL and 86.55 ± 1.26 µg/mL), respectively, relevant to Alzheimer’s disease. The es...

Based on our continuous effort to investigate chemistry and biology of the plant secondary metabolites, we were able to isolate a glycosidal flavonoid 1 from the Wild Egyptian Artichoke. The activity of dihydromyricetin 3-O-rhamnoside (sin. dihydromyricitrin, ampelopsin 3-O-rhamnoside) (1) against acetylcholinesterase (AChE) and butyrylcholinestera...

Series of synthetic coumarin derivatives (1‐16) were tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes linked to the pathology of Alzheimer’s disease (AD). Compound 16 was the most active AChE inhibitor with IC50 32.23 ± 2.91 µM, while the reference (galanthamine) had IC50= 1.85 ± 0.12 µM. Compounds 9 (IC5075....

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a key enzyme involved in cholesterol biosynthesis and one of the most important targets for the treatment of hy-percholesterolemia. A limited number of studies on the HMG-CoA reductase inhibitory potential of natural products are available. Thus, in the current study, we aimed to test the...

The ethanol extracts of five Origanum species: O. majorana L., O. onites L., O. syriacum L., O. vulgare subsp. hirtum (Link) Ietsw., and O. vulgare subsp. viride (Boiss.) Hayek, collected annually (each month), were investigated for their cholinesterase inhibition and antioxidant effects. The phytochemical composition of a total of 60 extracts was...

The extent to which proteins are protected from hydrogen deuterium exchange (HDX) provides valuable insight into their folding, dynamics and interactions. Characterised by mass spectrometry (MS), HDX benefits from negligible mass restrictions and exceptional throughput and sensitivity but at the expense of resolution. Exchange mechanisms which natu...

Cotinus coggygria Scop. (Anacardiaceae, syn: Rhus cotinus L.) is known as “boyacı sumağı, sarı boya, duman ağacı” in Turkish and “smoke tree” in English. It is commonly grown in Southern Europe and Anatolia. The leaves have been used due to its antiseptic, hemostatic, antipyretic, and wound healing effects as a 5% infusion in traditional medicine....

In recent decade, the entrance of α-N-heterocyclic thiosemicarbazones derivates (Triapne, COTI-2 and DpC) in clinical trials for cancer and HIV-1 has vastly increased the interests of medicinal chemists towards this class of organic compounds. In the given study, a series of eighteen new (3a-r) 3-ethoxy salicylaldehyde-based thiosemicarbazones (TSC...

In the present study, 23 novel carvacrol derivatives involving the amide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and tested in vitro as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. 2-(5-Isopropyl-2-methylphenoxy)-N-(quinolin-8-yl)acetamide (5v) revealed the highest inh...

Coumarins of synthetic or natural origins are an important chemical class exerting diverse pharmacological activities. In the present study, 26 novel O-alkylcoumarin derivatives were synthesized and have been tested at 100 µM for their in vitro inhibitory potential against acetylcholinesterase (AChE) and butyrlcholinesterase (BChE) targets which ar...

The phytochemical investigation of the extract ofVolutaria abyssinica(A. Rich.) C. Jeffrey (Asteraceae) resultedin the identification of the two sesquiterpene lactones,i.e.amberboin and lipidiol. Amberboin and lipidiol areinteresting tricyclic sesquiterpene lactone derivatives with a guaianolide skeleton. In the current study, theabsolute structure...

Appropriate therapeutic solutions against Staphylococcal infections are currently limited. To work out the complex task of challenging drug resistance in Staphylococcus aureus, new compounds with novel modes of action are required. In this study, we performed target-driven virtual screening to filter exhaustive phytochemical libraries that can inhi...

G Protein-Coupled Receptors (GPCRs) can form homodimer or constitute heterodimer/higher oligomeric clusters with other heptahelical GPCRs. In this article, multiscale molecular modeling approaches as well as experimental techniques which are used to study oligomerization of GPCRs are reviewed. In particular, the effect of dimerization/oligomerizati...

The active (D2HighR) and inactive (D2LowR) states of dimeric dopamine D2 receptor (D2R) models were investigated to clarify the binding mechanisms of the dopamine agonist bromocriptine, using Molecular Dynamics (MD) simulation. The aim of this comprehensive study was to investigate the critical effects of bromocriptine binding on each distinct rece...

Human α-glucosidase is an enzyme involved in the catalytic cleavage of the glucoside bond and involved in numerous functionalities of the organism, as well as in the insurgence of diabetes mellitus 2 and obesity. Thus, developing chemicals that inhibit this enzyme is a promising approach for the treatment of several pathologies. Small peptides such...

Background: Many natural products, particularly phenolic compounds, have been reported to have a strong inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the key enzymes in the pathology of Alzheimer’s disease (AD). Hypothesis: Therefore, we hypothesized that some xanthahumol, naringenin, and acyl phloroglucinol deriv...

AT1 antagonists is the most recent drug class of molecules against hypertension and they mediate their actions through blocking detrimental effects of angiotensin II (A-II) when acts on type I (AT1) A-II receptor. The effects of AT1 antagonists are not limited to cardiovascular diseases. AT1 receptor blockers may be used as potential anti-cancer ag...

Different Polygonum species have in vitro neuroprotective properties and are traditionally used for their anti-ageing benefits. In this context this work explored for the first time P. maritimum (sea knotgrass) as a potential source of natural products with industrial application as cognitive enhancers with anti-ageing potential. For that purpose m...

Angiotensin II receptor type 1 (AT1) antagonists are the most recent drug class against hypertension. Recently first crystal structure of AT1 receptor is deposited to the protein data bank (PDB ID: 4YAY). In this work, several molecular screening methods such as molecular docking and de novo design studies were performed and it is found that oxazol...

New coumaryl-carboxamide derivatives with the thiourea moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and their inhibitory activity against the human carbonic anhydrase (hCA) isoforms hCA I, II, VII and IX were evaluated. While the hCA I, II and VII isoforms were not inhibited by the investigated compoun...

The dopamine D2 Receptor (D2R) is a member of the G-Protein Coupled Receptor (GPCR) family and plays a critical role in neurotransmission activities in the human brain. Dysfunction in dopamine receptor signaling may lead to mental health illnesses such as schizophrenia and Parkinson’s disease. D2R is the target protein of the commonly used anti-psy...

The objective of this study was to evaluate the antioxidant effects of propolis, caffeic acid phenethyl ester (CAPE; active compound in propolis), and pollen on biochemical oxidative stress biomarkers in rat kidney tissue inhibited by Nω-nitro-L-arginine methyl ester (L-NAME). The biomarkers evaluated were paraoxonase (PON1), oxidative stress index...

Introduction Dopamine receptors perform various functions essential to vertebrate central nervous systems and they are the major targets of antipsychotic drugs. Our recent studies pioneered to perform molecular modeling studies of the dopamine D2 receptor (D2R), describing the mechanism and binding affinities of marketed antipsychotics into the act...

The intra-cavitary drug blockade of hERG1 channel has been extensively studied, both experimentally and theoretically. Structurally diverse ligands inadvertently block the hERG1 K⁺ channel currents lead to drug induced Long QT Syndrome (LQTS). Accordingly, designing either hERG1 channel openers or current activators, with the potential to target ot...

The dopamine receptor D2 (D2R) plays an important role in the human central nervous system and is a focal target of antipsychotic agents. The previously developed D2HighR and D2LowR dimeric models by our group are used to investigate the prediction of binding affinity of LY404,039 ligand and its binding mechanism within the catalytic domain. The ob...

In the present study, the changes that occur in rat liver tissue as a result of the use of grapeseed extract (GSE) and low level laser therapy (LLLT) in intraoral wound healing are analyzed using biochemical parameters. Diode laser application groups received 8 J/cm² dose LLLT once a day for 4 days (810 nm wavelength, continuous mode, 0.25 W, 9 sec...

The serotonin (5HT) transporter (SERT) is a member of neurotransmitter sodium symporter (NSS) family, which maintains neurotransmitter by reuptaking 5HT into synapses. Decrease in serotonin concentrations in synaptic clefts have been reported to cause psychological and neurological disorders. Therefore, inhibition of SERT is a potent strategy for t...

The objective of the present study was to evaluate the effects of propolis, pollen, and caffeic acid phenethyl ester (CAPE) on tyrosine hydroxylase (TH) activity and total RNA levels of Nω-nitro-L-arginine methyl ester (L-NAME) inhibition of nitic oxide synthase in the heart, adrenal medulla, and hypothalamus of hypertensive male Sprague dawley rat...

New thymol and carvacrol derivatives with the carbamate moiety were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. 5-isopropyl-2-methylphenyl(3-fluorophenyl)carbamate (29) was found to be the most potent AChE inhibitor with IC50 values of 2.22 μM, and 5-isopropyl-2-methylphe...

The dopamine D2 receptor (D2R) plays an important part in the human central nervous system and is considered to be a focal target of antipsychotic agents. It is structurally modeled in active and inactive states, in which homo-dimerization reaction of the D2R monomers is also applied. The ASP2314 (also known as ACR16) ligand, a D2R stabilizer, is u...

The Klotho is known as lifespan enhancing protein involved in antagonizing the effect of Wnt proteins. Wnt proteins are stem cell regulators, and uninterrupted exposure of Wnt proteins to the cell can cause stem and progenitor cell senescence, which may lead to aging. Keeping in mind the importance of Klotho in Wnt signaling, in silico approaches h...

PDE⸹ is a small protein that binds and controls the trafficking of KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) proteins which belongs to a family of small GTPases. KRAS holds a central position in the transduction of growth-promoting signals across the plasma membrane to regulate cell growth and differentiation. PDE⸹ regulates KRAS activity...

Bcl-2, an antiapoptotic protein from the Bcl family of proteins, is accepted as a potential target in cancer treatment since its oncogenic potential has been proven and is authenticated. Bcl-2 can be considered as the first identified apoptotic regulator of the principal pathway of apoptosis. This protein which conduce to tumor initiation, progress...

In this study, we investigated the ability of general anesthetic propofol (PR) to form inclusion complexes with modified β-cyclodextrins, including sulfobutylether-β-cyclodextrin (SBEβCD) and hydroxypropyl-β-cyclodextrin (HPβCD). The PR/SBEβCD and PR/HPβCD complexes were prepared and characterized, and the blood-brain barrier (BBB) permeation poten...

G-protein-coupled receptors (GPCRs) are targets of more than 30% of marketed drugs. Investigation on the GPCRs may shed light on upcoming drug design studies. In the present study, we performed a combination of receptor- and ligand-based analysis targeting the dopamine D2 receptor (D2R). The signaling pathway of D2R activation and the construction...

Poly(ADP-ribose) polymerase-1 (PARP-1) enzyme has critical roles in DNA replication repair and recombination. Thus, PARP-1 inhibitors play an important role in the cancer therapy. In the current study we have performed combination of in silico and in vitro studies in order to discover novel inhibitors against PARP-1 target. Structure-based virtual...

Dopamin analogs, urea and sulfamides

In the present study a series of urea and sulfamide compounds incorporating the tetralin scaffolds were synthesized and evaluated for their acetylcholinesterase (AChE), human carbonic anhydrase (CA, EC 4.2.1.1) isoenzyme I, and II (hCA I and hCA II) inhibitory properties. The urea and their sulfamide analogs were synthesized from the reactions of 2...

In this study, we investigated the cytotoxic effects of unmodified α-cyclodextrin (α-CD) and modified cyclodextrins, including trimethyl-β-cyclodextrin (TRIMEB) and hydroxypropyl-β-cyclodextrin (HPβCD), on immortalized murine microvascular endothelial (cEND) cells of the blood-brain barrier (BBB). A CellTiter-Glo® viability test, performed on the c...

In the present study a series of urea and sulfamide compounds incorporating the tetralin scaffolds were synthesized and evaluated for their acetylcholinesterase (AChE), human carbonic anhydrase (CA, EC 4.2.1.1) isoenzyme I, and II (hCA I and hCA II) inhibitory properties. The urea and their sulfamide analogs were synthesized from the reactions of 2...

The inhibitory effects of methoxyisobutylisonitrile (MIBI), diethylene triamine pentaacetic acid (DTPA), dimercaptosuccinic acid (DMSA) and metilendifosfonat (MDP) on human erythrocyte glucose 6-phosphate dehydrogenase (hG6PD) activity were investigated. For this purpose, hG6PD was initially purified 557-fold at a yield of 51.43% using 2',5'-adenos...

Dopamine D2 receptor plays a pivotal role in nervous systems. Its dysfunction leads to the schizophrenia, Parkinson’s diseases and drug addiction. Since the crystal structure of the D2R was not solved yet, discovering of potent and highly selective anti-psychotic drugs faces with main challenges. In the current study, we modeled the 3D structure of...

Assuming implicitly a 1:1 CD-cholesterol stoichiometry ratio, the CD-cholesterol complexes, as starting conformations, were subjected to 50-ns MD simulation with the MM-PBSA approach. During the first 20-25 ns, the ‘flip-flop’ motion of cholesterol within the CD hydrophobic channel was observed, thus indicating the prolonged ‘equilibration’ phase i...

Assuming implicitly a 1:1 CD-cholesterol stoichiometry ratio, the CD-cholesterol complexes, as starting conformations, were subjected to 50-ns MD simulation with the MM-PBSA approach. During the first 20-25 ns, the ‘flip-flop’ motion of cholesterol within the CD hydrophobic channel was observed, thus indicating the prolonged ‘equilibration’ phase i...

Assuming implicitly a 1:1 CD-cholesterol stoichiometry ratio, the CD-cholesterol complexes, as starting conformations, were subjected to 50-ns MD simulation with the MM-PBSA approach. During the first 20-25 ns, the ‘flip-flop’ motion of cholesterol within the CD hydrophobic channel was observed, thus indicating the prolonged ‘equilibration’ phase i...

We have recently reported GPCR model structures for the active and inactive states of the human dopamine D2 receptor (D2R) using adrenergic crystal structures as templates. Since the therapeutic concentrations of dopamine agonists that suppress the release of prolactin are the same as those that act at the high-affinity state of the D2 receptor (D2...

A series of hydroxylic compounds (1-10, NK-154 and NK-168) have been assayed for the inhibition of three physiologically relevant carbonic anhydrase isozymes, the cytosolic isozymes I, II and tumor-associated isozyme IX. The investigated compounds showed inhibition constants in the range of 0.068-4003, 0.012-9.9 and 0.025-115 μm at the hCA I, hCA I...

The angiotensin II type 1 receptor (AT1R) has been recently crystallized. A new era has emerged for the structure-based rational drug design and the synthesis of novel AT1R antagonists. In this critical review, the X-ray crystallographic data of commercially available AT1R antagonists in free form are analyzed and compared with the conformational a...

Mutated form (G52E) of diphtheria toxin (DT) CRM197 is an inactive and nontoxic enzyme. Here, we provided a molecular insight using comparative molecular dynamics (MD) simulations to clarify the influence of a single point mutation on overall protein and active-site loop. Post-processing MD analysis (i.e. stability, principal component analysis, hy...

Dengue virus is a major issue of tropical and sub-tropical regions. Dengue virus has been the cause behind the major alarming epidemics in the history with mass causalities from the decades. Unavailability of on-shelf drugs for the prevention of further proliferation of virus inside the human body results in immense number of deaths each year1. Thi...

Considering the parts that don’t interact well with the receptor protein, twenty essential amino acids were replaced with those parts or just added to angiotensin antagonists that are already used in antihypertensive drug industry. SP /XP/ IFD dockings were done with the recently discovered 4YAY. And it was seen that docking resutls were better com...

A series of Fmoc-Phe(4-aza-C60)-OH of fullerene amino acid derived peptides have been prepared by solid phase peptide synthesis, in which the terminal amino acid, Phe(4-aza-C60)-OH, is derived from the dipolar addition to C60 of the Fmoc-Nα-protected azido amino acids derived from phenylalanine: Fmoc-Phe(4-aza-C60)-Lys3-OH (1), Fmoc-Phe(4-aza-C60)-...

C-C chemokine receptor type 2 (CCR2) belongs to large GPCR family and it plays a critical role in cognitive function. Inhibition of CCR2 is important for autoimmune diseases, atherosclerosis, pain, and metabolic diseases. 3D structure of this receptor was not solved yet. In the current study, 3D structure of the CCR2 is predicted using recently sol...

PDEδ is a small protein that binds and controls the trafficking of RAS subfamily proteins. Its inhibition protects initiation of RAS signaling, and it is one of the common targets considered for oncological drug development. In this study, we used solved x-ray structures of inhibitor-bound PDEδ targets to investigate mechanisms of action of six ind...

Chemokine receptor 5 (CCR5) belongs to G protein coupled receptors (GPCRs) and plays an important role in treatment of human immunodeficiency virus (HIV) infection since HIV uses CCR5 protein as a co-receptor. Recently, the crystal structure of CCR5-bound complex with an approved anti-retroviral drug (maroviroc) was resolved. During the crystalliza...

Carbonic anhydrase type IX (CA IX) enzyme is mostly over expressed in different cancer cell lines and tumor tissues. Potent CA IX inhibitors can be effective for adjusting the pH imbalance in tumor cells. In the present work, we represented the successful application of high throughput virtual screening (HTVS) of large dataset from ZINC database in...

Abstract A series of hydroxy and phenolic compounds have been assayed for the inhibition of two physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic human isozymes I and II. The investigated molecules showed inhibition constants in the range of 1.07-4003 and 0.09-31.5 μM at the hCA I and hCA II enzymes, respectively....

Homology model structures of the dopamine D2 receptor (D2R) were generated starting from the active and inactive states of [Formula: see text]2-adrenergic crystal structure templates. To the best of our knowledge, the active conformation of D2R was modeled for the first time in this study. The homology models are built and refined using MODELLER an...

The rational design of high-affinity inhibitors of poly-ADP-ribose polymerase-1 (PARP-1) is at the heart of modern anti-cancer drug design. While relevance of enzyme to DNA repair processes in cellular environment is firmly established, the structural and functional understanding of the main determinants for high-affinity ligands controlling PARP-1...

Opioid G protein-coupled receptors (GPCRs) have been implicated in modulating pain, addiction, psychotomimesis, mood and memory, among other functions. We have employed the recently reported crystal structure of the human κ-opioid receptor (κ-OR) and performed molecular dynamics (MD), free energy, and ab initio calculations to elucidate the binding...

A series of sulfamoylcarbamates and sulfamides were evaluated for hCA I and hCA II inhibitory properties. Molecular modelling and experimental studies showed that all compounds are sufficiently active as carbonic anhydrase inhibitors.

Monte Carlo simulations were employed to gain insight on HCN adsorption mechanism on LTA zeolites with different alkali metal cations, Li + , Na + , and K + . Adsorption isotherms were calculated at four different temperatures at and above the normal boiling point of HCN. Results show that adsorption capacity depends on the type of the extraframewo...

Because of their high ion exchange capacity, silver exchanged LTA (Ag-LTA) zeolites can be incorporated in polymeric materials as antibacterial agents for various purposes such as preventing biofouling in water treatment membranes due to the formation of microorganisms like bacteria, algae. Ag-LTA can be prepared by exchanging extra-framework Na+ i...