Publications

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“Drug-likeness” properties of natural compounds

Published in Physical Sciences Reviews, 2019

Our previous work was focused on the fundamental physical and chemical concepts behind “drug-likeness” and “natural product (NP)-likeness”. Herein, we discuss further details on the concepts of “drug-likeness”, “lead-likeness” and “NP-likeness”. The discussion will first focus on NPs as drugs, then a discussion of previous studies in which the complexities of the scaffolds and chemical space of naturally occurring compounds have been compared with synthetic, semisynthetic compounds and the Food and Drug Administration-approved drugs. This is followed by guiding principles for designing “drug-like” natural product libraries for lead compound discovery purposes. In addition, we present a tool for measuring “NP-likeness” of compounds and a brief presentation of machine-learning approaches. A binary quantitative structure-activity relationship for classifying drugs from nondrugs and natural compounds from nonnatural ones is also described. While the studies add to the plethora of recently published works on the “drug-likeness” of NPs, it no doubt increases our understanding of the physicochemical properties that make NPs fall within the ranges associated with “drug-like” molecules.

Recommended citation: Fidele Ntie-Kang, Kennedy D Nyongbela, Godfred A Ayimele, Suhaib Shekfeh, “Drug-likeness” properties of natural compounds. 2019, Physical Sciences Reviews, 11, 20180169. https://www.degruyter.com/document/doi/10.1515/psr-2018-0169/html

Novel Piperazine Amides of Cinnamic Acid Derivatives as Tyrosinase Inhibitors.

Published in Letters in Drug Design and Discovery, 2019

A series of novel cinnamic acid piperazine amide derivatives has been designed and synthesized, and their biological activities were also evaluated as potential tyrosinase inhibitors. Compounds 9, 11 and 17 showed the most potent biological activity (IC50 = 66.5, 61.1 and 66 µM, respectively). In silico docking simulation was performed to position compound 11 into the Agaricus bisporus mushroom tyrosinase’s active site to determine the putative binding interactions. Results and Conclusion The results indicated that compound 11 could serve as a promising lead compound for further development of potent tyrosinase inhibitors.

Recommended citation: Z. T. Gur, F. S. Senol, S. Shekfeh, I. E. Orhan, E. Banglu, B. Caliskan, Novel Piperazine Amides of Cinnamic Acid Derivatives as Tyrosinase Inhibitors. 2019, Letters in Drug Design and Discovery, 16, 36-44. https://www.eurekaselect.com/article/89874

A Multi-step Virtual Screening Protocol for the Identification of Novel Non-acidic Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) Inhibitors.

Published in ChemMedChem, 2018

Microsomal prostaglandin E2 synthase-1 (mPGES-1) is a potential therapeutic target for the treatment of inflammatory diseases and certain types of cancer. To identify novel scaffolds for mPGES-1 inhibition, we applied a virtual screening (VS) protocol that comprises molecular docking, fingerprints-based clustering with diversity-based selection, protein–ligand interactions fingerprints, and molecular dynamics (MD) simulations with molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The hits identified were carefully analyzed to ensure the selection of novel scaffolds that establish stable interactions with key residues in the mPGES-1 binding pocket and inhibit the catalytic activity of the enzyme. As a result, we discovered two promising chemotypes, 4-(2-chlorophenyl)-N-[(2-{[(propan-2-yl)sulfamoyl]methyl}phenyl)methyl]piperazine-1-carboxamide (6) and N-(4-methoxy-3-{[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]sulfamoyl}phenyl)acetamide (8), as non-acidic mPGES-1 inhibitors with IC50 values of 1.2 and 1.3 μm, respectively. Minimal structural optimization of 8 resulted in three more compounds with promising improvements in inhibitory activity (IC50: 0.3–0.6 μm). The unprecedented chemical structures of 6 and 8, which are amenable to further derivatization, reveal a new and attractive approach for the development of mPGES-1 inhibitors with potential anti-inflammatory and anticancer properties

Recommended citation: Dr. Suhaib Shekfeh, Prof. Burcu Calıskan, Katrin Fischer, Tansu Yalcın, Dr. Ulrike Garscha, Prof. Oliver Werz, Prof. Erden Banoglu; A Multi-step Virtual Screening Protocol for the Identification of Novel Non-acidic Microsomal Prostaglandin-E2 Synthase-1 mPGES-1 Inhibitors. 2019, ChemMedChem, First published : 11 December 2018 https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.201800701

““Drug-Likeness” versus “Natural Product-Likeness”

Published in Preprints, 2018

We discuss further details on the concepts of “drug-likeness”, “lead-likeness”, and “natural product-likeness”. The discussion will first focus on natural products as drugs, then a discussion of previous studies in which the complexities of the scaffolds and chemical space of naturally occurring compounds have been compared with synthetic, semi-synthetic compounds and FDA-approved drugs. This is followed by guiding principles for designing “drug-like” natural product libraries for lead compound discovery purposes. We end up by presenting a tool for measuring “natural product-likeness” of compounds and a brief presentation of machine learning approaches and a binary quantitative structure-activity relationship (QSAR) for classifying drugs from non-drugs and natural compounds from non-natural ones, respectively.

Recommended citation: Ntie-Kang, F.; Nyongbela, K.D.; Ayimele, G.A.; Shekfeh, S. “Drug-Likeness” versus “Natural Product-Likeness”. Preprints 2018, 2018110561. https://www.preprints.org/manuscript/201811.0561/v1

Pteryxin: A promising butyrylcholinesterase-inhibiting coumarin derivative from Mutellina purpurea.

Published in Food and Chemical Toxicology, 2017

Pteryxin is a dihydropyranocoumarin derivative found in Apiaceae family. In this study, pteryxin, which was previously isolated from the fruits of Mutellina purpurea, was investigated for its inhibitory potential against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which are the key enzymes in the pathology of Alzheimer’s disease (AD). The compound was tested in vitro using ELISA microplate reader at 100 μg/ml and found to cause 9.30 ± 1.86% and 91.62 ± 1.53% inhibition against AChE and BChE, respectively. According to our results, pteryxin (IC50 = 12.96 ± 0.70 μg/ml) was found to be a more active inhibitor of BChE than galanthamine (IC50 = 22.16 ± 0.91 μg/ml; 81.93± 2.52% of inhibition at 100 μg/ml). Further study on pteryxin using molecular docking experiments revealed different possible binding modes with both polar and hydrophobic interactions inside the binding pocket of BChE. Top docking solution points out to the formation of two hydrogen bonds with the catalytic residues S198 and H438 of BChE as well as a strong pi-pi stacking with W231.

Recommended citation: I. E. Orhan, F. Senol, S. Shekfeh, K. Skalicka-Wozniakc, E. Banoglu, Pteryxin - A promising butyrylcholinesterase-inhibiting coumarin derivative from Mutellina purpurea. 2017, Food. Chem. Tox., 109, 970-974. https://www.sciencedirect.com/science/article/abs/pii/S0278691517301096

Synthesis and biological testing of novel pyridoisothiazolones as histone acetyltransferase inhibitors.

Published in Bioorganic & Medicinal Chemistry, 2012

a combination of database screening, synthesis and in vitro testing to identify novel histone acetyltransferase (HAT) inhibitors. The National Cancer Institute compound collection (NCI) and several commercial databases were filtered by similarity-based virtual screening to find new HAT inhibitors. Employing the recombinant HAT p300/CBP-associated factor (PCAF) and two different histone substrates for screening, pyridoisothiazolones were identified as inhibitors of human PCAF. Due to the limited solubility of the initial hits, we synthesized and tested them on PCAF. The compounds inhibit the proliferation of cancer cells. In summary, valuable chemical tools and potential lead candidates for new anticancer agents directed against HATs as new targets

Recommended citation: S. D. Furdas, S. Shekfeh, E. Bissinger, J. Wagner, C. H. Arrowsmith, M. M. Mangos, V. Valkov, M. Hendzel, M. Jung, W. Sippl. Synthesis and biological testing of novel pyridoisothiazolones as histone acetyltransferase inhibitors. Bioorganic Medicinal Chemistry 19, 2011, 3678-3689 https://www.sciencedirect.com/science/article/abs/pii/S0968089611000927

Rhodaninecarboxylic acids as novel inhibitors of histoneacetyltransferases.

Published in MedChemComm / RSC Medicinal Chemistry, 2012

Histone acetyltransferases (HATs) are promising epigenetic drug targets and are involved in the pathogenesis of a wide range of diseases. We carried out a virtual screening based on inhibitors of serotonin N-acetyltransferase and identified novel inhibitors of the HATPCAF with a 2-thioxo-4-thiazolidinone (rhodanine) scaffold attached to a long chain carboxylic acid. Their binding mode was studied by means of docking and molecular dynamics simulations. Structure–activity studies were performed by organic synthesis and in vitro testing in an antibody based biochemical assay showing similar inhibition on the HATs PCAF, Gcn5, CBP and p300 in vitro. In contrast, a pyridoisothiazolone reference inhibitor is more potent on CBP and to some extent on PCAF but less potent on Gcn5. Structural elements were identified that provide the basis for further optimization of the new inhibitors.

Recommended citation: S. D. Furdas, S. Shekfeh, S. Kannan, W. Sippl, M.Jung, Rhodanine carboxylic acids as novel inhibitors of Histone acetyltransferases. Med. Chem. Commun. 2012, 3, 305-311 https://pubs.rsc.org/en/content/articlelanding/2012/md/c2md00211f

From cosubstrate similarity to inhibitor diversity-inhibitors of ADP-ribosyltransferases from kinase inhibitor screening.

Published in Molecular BioSystems, 2011

ADP-ribosyltransferases (ADP-RTs) use NAD+ to transfer an ADP-ribosyl group to target proteins. Although some ADP-RTs are bacterial toxins only few inhibitors are known. Here we present the development of fluorescence-based assays and a focussed library screening using kinase inhibitors as a new approach towards inhibitors of ADP-RTs. Docking and GBSA scoring were used to understand the interactions between the toxin proteins and the inhibitors.

Recommended citation: B. Maurer, U. Mathias, S. Shekfeh, P. Papatheodorou, J. Orth, T. Jank, C. Schwan, W. Sippl, K. Aktories, M. Jung. From cosubstrate similarity to inhibitor diversity-inhibitors of ADP-ribosyltransferases from kinase inhibitor screening. Mol. BioSyst., 2011,7, 799-808. https://pubs.rsc.org/en/content/articlelanding/2011/mb/c0mb00151a