Publications by authors named "Somayeh Pirhadi"

22 Publications

  • Page 1 of 1

The natural-based optimization of kojic acid conjugated to different thio-quinazolinones as potential anti-melanogenesis agents with tyrosinase inhibitory activity.

Bioorg Med Chem 2021 Apr 27;36:116044. Epub 2021 Jan 27.

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

Melanin pigment and melanogenesis are a two-edged sword. Melanin has a radioprotection role while melanogenesis has undesirable effects. Targeting the melanogenesis pathway, a series of kojyl thioether conjugated to different quinazolinone derivatives were designed, synthesized, and evaluated for their inhibitory activity against mushroom tyrosinase. All the synthesized compounds were screened for their anti-tyrosinase activity and all derivatives displayed better potency than kojic acid as the positive control. In this regard, 5j and 5h as the most active compounds showed an IC value of 0.46 and 0.50 µM, respectively. In kinetic evaluation against tyrosinase, 5j depicted an uncompetitive inhibition pattern. Designed compounds also exhibited mild antioxidant capacity. Moreover, 5j and 5h achieved good potency against the B16F10 cell line to reduce the melanin content, whilst showing limited toxicity against malignant cells. The proposed binding mode of new inhibitors evaluated through molecular docking was consistent with the results of structure-activity relationship analysis.
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http://dx.doi.org/10.1016/j.bmc.2021.116044DOI Listing
April 2021

Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met.

Sci Rep 2021 Feb 11;11(1):3644. Epub 2021 Feb 11.

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

Aberrant activation of c-Met signalling plays a prominent role in cancer development and progression. A series of 12 imidazo [1,2-α] pyridine derivatives bearing 1,2,3-triazole moiety were designed, synthesized and evaluated for c-Met inhibitory potential and anticancer effect. The inhibitory activity of all synthesized compounds against c-Met kinase was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay at the concentration range of 5-25 µM. Derivatives 6d, 6e and 6f bearing methyl, tertiary butyl and dichloro-phenyl moieties on the triazole ring, respectively, were the compounds with the highest potential. They significantly inhibited c-Met by 55.3, 53.0 and 51.3%, respectively, at the concentration of 25 µM. Synthetic compounds showed antiproliferative effects against lung (EBC-1) and pancreatic cancer cells (AsPc-1, Suit-2 and Mia-PaCa-2) expressing different levels of c-Met, with IC values as low as 3.0 µM measured by sulforhodamine B assay. Active derivatives significantly blocked c-Met phosphorylation, inhibited cell growth in three-dimensional spheroid cultures and also induced apoptosis as revealed by Annexin V/propidium iodide flow cytometric assay in AsPc-1 cells. They also inhibited PDGFRA and FLT3 at 25 µM among a panel of 16 kinases. Molecular docking and dynamics simulation studies corroborated the experimental findings and revealed possible binding modes of the select derivatives with target receptor tyrosine kinases. The results of this study show that some imidazopyridine derivatives bearing 1,2,3-triazole moiety could be promising molecularly targeted anticancer agents against lung and pancreatic cancers.
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http://dx.doi.org/10.1038/s41598-021-83069-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878917PMC
February 2021

Design and characterization of a recombinant immunotoxin for targeted therapy of breast cancer cells: In vitro and in silico analyses.

Life Sci 2021 Jan 7;265:118866. Epub 2020 Dec 7.

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

Aims: GnRH-DFF40 (gonadotropin releasing hormone-DNA fragmentation factor 40) humanized recombinant immunotoxin serves as a prospective candidate for targeted therapy of malignancies with over-expressed gonadotropin releasing hormone receptor (GnRHR). In this study, we attempted to generate a GnRH-based chimeric protein composed of human DFF40 fused with GnRH which encodes an apoptotic nuclease and specifically targets cancer cells displaying GnRH receptor overexpression.

Materials And Methods: A codon optimized, synthetic GnRH-DFF40 fusion gene and its single counterpart (DFF40) were constructed in pET28a expression vector. Cytotoxicity of these expressed proteins were evaluated on three breast cancer cell lines (MCF7, MDA-MB231, and SKBR3). The stability and biological activity of the recombinant proteins were investigated in the treated cell line and cell-free system. Also, the ability of this fusion and its single form in inducing apoptosis, and inhibiting metastasis and migration were evaluated by flow cytometry, migration assay and wound healing analysis, respectively. In silico analyses were also done to understand the specific interactions between GnRH and its receptor.

Key Findings: GnRH-DFF40 fusion protein and DFF40 were successfully expressed. The purified chimeric protein showed dose-dependent cytotoxicity against all three cell lines. The recombinant fusion protein was biologically active with nucleolytic functionality and apoptosis induction ability. Moreover, the fusion could inhibit the invasion property of MDA-MB-231 cells. In silico analysis also showed that four residues from GnRH domain and 11 GnRHR residues had the most interaction sites for specific targeted delivery of the immunotoxin in cancer cells.

Significance: Fusion construct could be a prospective candidate for targeted therapy of cancers upregulating GnRH receptor.
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http://dx.doi.org/10.1016/j.lfs.2020.118866DOI Listing
January 2021

Novel 2-amino-1,4-naphthoquinone hybrids: Design, synthesis, cytotoxicity evaluation and in silico studies.

Bioorg Med Chem 2020 11 28;28(21):115718. Epub 2020 Aug 28.

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

In the present work, a novel series of 2-amino-1,4-naphthoquinones bearing oxyphenyl moiety (5a-5m) were designed and synthesized via a two-step route and evaluated for their in vitro cytotoxic activity against three different cancer cell lines (MCF-7, HL-60 and U937) and normal human cell line (HEK-293) by MTT assay. Compounds 5b (4-nitro-benzyl-) and 5k (4-bromo-benzyl-) were identified to possess the highest cytotoxic activity against MCF-7 cancerous cells (IC values of 27.76 and 27.86 μM, respectively). At the same time, none of the compounds exert significant toxicity against HEK-293 normal human kidney cells. Cell cycle analysis showed that the selected derivatives increased the population of MCF-7 cells in the S phase at 25 and 50 μM concentrations. Annexin V-FITC/PI staining assay also confirmed that compounds 5b and 5k induced apoptosis in the cell death pathway. Molecular docking and molecular dynamics studies were also performed to evaluate the probable interactions between the hybrids and human ATP binding domain of topo IIα protein. Our findings may provide new insight for further development of novel naphthoquinone-containing compounds.
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http://dx.doi.org/10.1016/j.bmc.2020.115718DOI Listing
November 2020

Antidiabetic and cytotoxic polyhydroxylated oleanane and ursane type triterpenoids from Salvia grossheimii.

Bioorg Chem 2020 11 19;104:104297. Epub 2020 Sep 19.

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

Two polyhydroxylated oleanane and seven ursane triterpenoids were isolated from aerial parts of Salvia grossheimii. The chemical structures of the undescribed triterpenoids (1-6) were characterized using 1 and 2 D NMR and ESI-MS spectral data as; 2α, 3β, 11α -trihydroxy-olean-12- ene (1), 2α, 3β, 11α-trihydroxy-olean-18-ene (2), 2α- acetoxy-urs-12-ene-3β, 11α, 20β-triol (3), 3-keto-urs-12-ene-1β, 11α, 20β -triol (4), 2α, 3β-diacetoxy-urs-12-ene-1β, 11α, 20β -triol (5), and 3β-acetoxy-urs-12-ene-1β, 11α, 20β -triol (6). All compounds were evaluated for the in vitro α-glucosidase inhibitory and cytotoxic activities against MCF-7 human cancer cell line. Compounds 1, 2, 4, and 6 showed in vitro α-glucosidase inhibitory activity with IC = 43.6-198.4 µM, which were more potent than the antidiabetic medicine, acarbose. The remaining compounds; 3, and 7-9 showed potent cytotoxic activity (IC = 6.2-31.9 µM) against the cancerous cell line, while the potent α-glucosidase inhibitors were inactive. Molecular docking analysis and kinetic studies were applied to investigate the structure activity relationships and mechanisms of the human and Saccharomyces cerevisiae α-glucosidase inhibitory of the purified compounds. Comparing the high cytotoxicity and α-glucosidase inhibitory of the oleanane and ursane type triterpenoids suggest them as potential lead compounds for further research in anticancer and antidiabetic research.
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http://dx.doi.org/10.1016/j.bioorg.2020.104297DOI Listing
November 2020

Molecular dynamics simulation of siRNA loading into a nanoemulsion as a potential carrier.

J Mol Model 2020 Jul 25;26(8):215. Epub 2020 Jul 25.

Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran.

Nanoemulsions are used as drug delivery carriers for different types of systems. Nanoemulsions can enhance solubilization property of poorly water-soluble drugs and increase the drug loading. In this study, we used a nanoemulsion composed of benzalkonium chloride as surfactant, cyclohexane as oil phase, and ethanol as co-surfactant in water, to load small interfering RNA (siRNA) molecule. The system was investigated by three coarse-grained molecular dynamics simulations. The results showed that siRNA attached to benzalkonium chloride on the surface of the nanoemulsion and the oil beads were located in the hydrophobic core of the nanoemulsion, which made its size larger. The ethanol beads distributed throughout the system and did not enter to the hydrophilic shell of the nanoemulsion. The nanoemulsion structure was a compact prolate ellipsoid shape, before and after carrying the siRNA. The average value of radius of gyration of the nanoemulsion was 1.68 nm before and after joining siRNA and the average value of physical radius was 2.17 nm.
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http://dx.doi.org/10.1007/s00894-020-04471-9DOI Listing
July 2020

A Series of Benzylidenes Linked to Hydrazine-1-carbothioamide as Tyrosinase Inhibitors: Synthesis, Biological Evaluation and Structure-Activity Relationship.

Chem Biodivers 2020 Aug 3;17(8):e2000285. Epub 2020 Aug 3.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, 71348, Shiraz, Iran.

Tyrosinase is a type 3 copper enzyme responsible for skin pigmentation disorders, skin cancer, and enzymatic browning of vegetables and fruits. In the present article, 12 small molecules of 2-benzylidenehydrazine-1-carbothioamide were designed, synthesized and evaluated for their anti-tyrosinase activities followed by molecular docking and pharmacophore-based screening. Among synthesized thiosemicarbazone derivatives, one compound, (2E)-2-[(4-nitrophenyl)methylidene]hydrazine-1-carbothioamide, is the strongest inhibitor of mushroom tyrosinase with IC of 0.05 μM which demonstrated a 128-fold increase in potency compared to the positive control. Kinetic studies also revealed mix type inhibition by this compound. Docking studies confirmed the complete fitting of the synthesized compounds into the tyrosinase active site. The results underline the potential of 2-benzylidenehydrazine-1-carbothioamides as potent pharmacophore to extend the tyrosinase inhibition in drug discovery.
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http://dx.doi.org/10.1002/cbdv.202000285DOI Listing
August 2020

Dual potent c-Met and ALK inhibitors: from common feature pharmacophore modeling to structure based virtual screening.

J Recept Signal Transduct Res 2020 Aug 3;40(4):357-364. Epub 2020 Mar 3.

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

Everyday plenty of people succumb to various forms of cancer across the world and it stands as one of the main reasons of death in our today's life. Receptor tyrosine kinases (RTKs) are a class of receptors involved in cancer progression. Since aberrant signaling has critical roles in cancer, both c-Met and ALK enzymes are regarded as attractive oncology targets for therapeutic objects. A number of potent dual inhibitors of c-Met and ALK are reported in literature that in the present work we based them to construct multiple common feature pharmacophore models and then applied them for ligand-based virtual screening. The score values of the models ranged from 22.489 to 28.169. The retrieved compounds from virtual screening were subjected to the docking study and the interaction pattern of common hits between two enzymes with high predicted affinity has been investigated. To this end, common hit compound ZINC000223394281 (z1) was directed to the molecular dynamics study and the results indicated that the hydrogen bond interaction between this compound and Asp1222 was mostly stable during the equilibrium time range. The life time of hydrogen bond made between the complex of ALK and Met1199 was also stable in 63%.
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http://dx.doi.org/10.1080/10799893.2020.1735418DOI Listing
August 2020

One-pot synthesis of thioxo-tetrahydropyrimidine derivatives as potent β-glucuronidase inhibitor, biological evaluation, molecular docking and molecular dynamics studies.

Bioorg Med Chem 2020 04 6;28(7):115359. Epub 2020 Feb 6.

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

A series of N,N-diethyl phenyl thioxo-tetrahydropyrimidine carboxamide have been synthesized and investigated for their β-glucuronidase inhibitory activities. All molecules exhibited excellent inhibition with IC values ranging from 0.35 to 42.05 µM and found to be even more potent than the standard d-saccharic acid. Structure-activity relationship analysis indicated that the meta-aryl-substituted derivatives significantly influenced β-glucuronidase inhibitory activities while the para-substitution counterpart outperforming moderate potency. The most potent compound in this series was 4g bearing thiophene motif with IC of 0.35 ± 0.09 µM. To verify the SAR, molecular docking and molecular dynamics studies were also performed.
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http://dx.doi.org/10.1016/j.bmc.2020.115359DOI Listing
April 2020

Study of the mechanism of action, molecular docking, and dynamics of anticancer terpenoids from .

J Recept Signal Transduct Res 2020 Feb 8;40(1):24-33. Epub 2020 Jan 8.

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

Among specialized metabolites, terpenoids are well-known for their cytotoxic activity. Several of them have been isolated from sage plants and assayed for their potential therapeutic use against cancer. In this study, we report the effects of three potent anticancer terpenoids previously isolated from , including geranyl farnesol (), sahandinone (), and 4-dehydrosalvilimbinol () on cancer cell cycle alterations and reactive oxygen species (ROS) production. Interactions of compounds with topoisomerase I were also investigated by using molecular docking and dynamics simulation. Accumulation of cells in sub-G1 phase of the cell cycle indicated that all tested compounds induce apoptosis in MOLT-4 cancer cells. Measurement of ROS production demonstrated that this mechanism is not involved in the induction of apoptosis. We suggest topoisomerase I inhibition as the mechanism of cytotoxic activity of compounds based on docking and molecular dynamics (MD) calculations. These natural terpenoids could be considered as good candidates for further development as anticancer agents.
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http://dx.doi.org/10.1080/10799893.2019.1710847DOI Listing
February 2020

Clustering and Sampling of the c-Met Conformational Space: A Computational Drug Discovery Study.

Comb Chem High Throughput Screen 2019 ;22(9):635-648

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

Background: c-Met kinase plays a critical role in a myriad of human cancers, and a massive scientific work was devoted to design more potent inhibitors.

Objective: In this study, 16 molecular dynamics simulations of different complexes of potent c-Met inhibitors with U-shaped binding mode were carried out regarding the dynamic ensembles to design novel potent inhibitors.

Methods: A cluster analysis was performed, and the most representative frame of each complex was subjected to the structure-based pharmacophore screening. The GOLD docking program investigated the interaction energy and pattern of output hits from the virtual screening. The most promising hits with the highest scoring values that showed critical interactions with c-Met were presented for ADME/Tox analysis.

Results: The screening yielded 45,324 hits that all of them were subjected to the docking studies and 10 of them with the highest-scoring values having diverse structures were presented for ADME/Tox analyses.

Conclusion: The results indicated that all the hits shared critical Pi-Pi stacked and hydrogen bond interactions with Tyr1230 and Met1160 respectively.
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http://dx.doi.org/10.2174/1386207322666191024103902DOI Listing
September 2020

Prediction of cytotoxic activity of a series of 1H-pyrrolo[2,3-b]pyridine derivatives as possible inhibitors of c-Met using molecular fingerprints.

J Recept Signal Transduct Res 2019 Aug 28;39(4):295-303. Epub 2019 Oct 28.

Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA.

Cancer is a leading cause of death all over the world. HGF/MET signaling pathway is involved in many cancers and its inhibition has great potential as an effective therapeutic intervention. A series of 1H-pyrrolo [2,3-b]pyridine derivatives has recently been identified with cytotoxic activity, and most of them exhibited considerable potencies with IC values under 10 µM. The present study was carried out with the specific aim to shed light upon the quantitative structure activity relationship (QSAR) to design and predict the activity of new potent inhibitors using molecular fingerprints and some 2D and 3D descriptors. The built model was statistically significant in terms of = 0.90 and = 0.91 values. Fingerprint PubchemFP759 (1-chloro-2-methylbenzene) was the most effective fragment in the biological activity and just appeared in the most active compound 7j with a pIC value of 8.0. A similarity search study was applied based on compounds 7c and 17e, with reported inhibitory activity against c-Met kinase, which showed that also other compounds could possess similar effects against c-Met enzyme. The most promising compound 7g-cl was subjected to docking and molecular dynamics simulation. Two hydrogen bonds between Lys1110, Met1160, and 7g-cl were stable during the equilibrium time range. The suggested modifications might be considered in future studies to design more efficient anticancer agents.
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http://dx.doi.org/10.1080/10799893.2019.1676258DOI Listing
August 2019

Metronidazole aryloxy, carboxy and azole derivatives: Synthesis, anti-tumor activity, QSAR, molecular docking and dynamics studies.

Bioorg Med Chem 2019 01 4;27(2):305-314. Epub 2018 Dec 4.

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

A series of novel metronidazole aryloxy, carboxy and azole derivatives has been synthesized and their cytotoxic activities on three cancer cell lines were evaluated by MTT assay. Compounds 4m, 4l and 4d showed the most potent cytotoxic activity (ICs less than 100 µg/mL). Apoptosis was also detected for these compounds by flow cytometry. Docking studies were performed in order to propose the probable target protein. In the next step, molecular dynamics simulation was carried out on the proposed target protein, focal adhesion kinase (FAK, PDB code: 2ETM), bound to compound 4m. As, 4m showed a potent cytotoxic activity and an acceptable apoptotic effect, it can be a potential anticancer candidate that may work through inhibition of FAK.
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http://dx.doi.org/10.1016/j.bmc.2018.12.003DOI Listing
January 2019

Dynamic structure based pharmacophore modeling of the Acetylcholinesterase reveals several potential inhibitors.

J Biomol Struct Dyn 2019 Apr 17;37(7):1800-1812. Epub 2018 May 17.

c School of Chemistry , University College of Science, University of Tehran , Tehran , Iran.

Acetylcholinesterase is a critical enzyme that regulates neurotransmission by catalyzing the breakdown of neurotransmitter acetylcholine in synapses of the nervous system. It is an important target for therapeutic drugs that treat Alzheimer's disease. Since, the degree of flexibility of the side chains of the residues in the active-site gorge of Acetylcholinesterase is diverse it results in different bound ligand conformations. The side-chain conformations of Ser293, Tyr341, Leu76, and Val73 are flexible, while the side-chain conformations of Tyr72, Tyr 124, Ser125, Phe295, and Arg296 appear to be fixed. In this study, multi-conformation dynamic pharmacophore models from the donepezyl-binding pocket based on highly populated structures chosen from molecular dynamics simulations were used for screening compounds that can properly bind acetylcholinesterase. Based on these structures, three pharmacophore models were generated. Consequently, 14 hits were retrieved as final candidates by utilizing virtual screening of ZINC database and molecular docking.
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http://dx.doi.org/10.1080/07391102.2018.1468281DOI Listing
April 2019

Identification of new potential HIV-1 reverse transcriptase inhibitors by QSAR modeling and structure-based virtual screening.

J Recept Signal Transduct Res 2018 Feb 19;38(1):37-47. Epub 2017 Dec 19.

a Department of Chemistry , University of Zabol , Zabol , Iran.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique antiviral potency, high specificity and low toxicity in antiretroviral combination therapies which are used to treat HIV. To design more specific HIV-1 inhibitors, 218 diverse non-nucleoside reverse transcriptase inhibitors with their EC values were collected. Then, different types of molecular descriptors were calculated. Also, genetic algorithm (GA) and enhanced replacement methods (ERM) were used as the variable selection approaches to choose more relevant features. Based on selected descriptors, a classification support vector machine (SVM) model was constructed to categorize compounds into two groups of active and inactive ones. The most active compound in the set was docked and was used as the input to the Pharmit server to screen the Molport and PubChem libraries by constructing a structure-based pharmacophore model. Shape filters for the protein and ligand as well as Lipinski's rule of five have been applied to filter out the output of virtual screening from pharmacophore search. Three hundred and thirty-four compounds were finally retrieved from the virtual screening and were fed to the previously constructed SVM model. Among them, the SVM model rendered seven active compounds and they were also analyzed by docking calculations and ADME/Tox parameters.
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http://dx.doi.org/10.1080/10799893.2017.1414844DOI Listing
February 2018

Open source molecular modeling.

J Mol Graph Model 2016 09 30;69:127-43. Epub 2016 Jul 30.

Department of Computational and Systems Biology, University of Pittsburgh, United States. Electronic address:

The success of molecular modeling and computational chemistry efforts are, by definition, dependent on quality software applications. Open source software development provides many advantages to users of modeling applications, not the least of which is that the software is free and completely extendable. In this review we categorize, enumerate, and describe available open source software packages for molecular modeling and computational chemistry. An updated online version of this catalog can be found at https://opensourcemolecularmodeling.github.io.
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http://dx.doi.org/10.1016/j.jmgm.2016.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037051PMC
September 2016

Alignment independent 3D-QSAR, quantum calculations and molecular docking of Mer specific tyrosine kinase inhibitors as anticancer drugs.

Saudi Pharm J 2016 Mar 31;24(2):197-212. Epub 2015 Mar 31.

Drug Design in Silico Laboratory, Chemistry Faculty, K.N. Toosi University of Technology, Tehran, Iran.

Mer receptor tyrosine kinase is a promising novel cancer therapeutic target in many human cancers, because abnormal activation of Mer has been implicated in survival signaling and chemoresistance. 3D-QSAR analyses based on alignment independent descriptors were performed on a series of 81 Mer specific tyrosine kinase inhibitors. The fractional factorial design (FFD) and the enhanced replacement method (ERM) were applied and tested as variable selection algorithms for the selection of optimal subsets of molecular descriptors from a much greater pool of such regression variables. The data set was split into 65 molecules as the training set and 16 compounds as the test set. All descriptors were generated by using the GRid INdependent descriptors (GRIND) approach. After variable selection, GRIND were correlated with activity values (pIC50) by PLS regression. Of the two applied variable selection methods, ERM had a noticeable improvement on the statistical parameters of PLS model, and yielded a q (2) value of 0.77, an [Formula: see text] of 0.94, and a low RMSEP value of 0.25. The GRIND information contents influencing the affinity on Mer specific tyrosine kinase were also confirmed by docking studies. In a quantum calculation study, the energy difference between HOMO and LUMO (gap) implied the high interaction of the most active molecule in the active site of the protein. In addition, the molecular electrostatic potential energy at DFT level confirmed results obtained from the molecular docking. The identified key features obtained from the molecular modeling, enabled us to design novel kinase inhibitors.
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http://dx.doi.org/10.1016/j.jsps.2015.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792907PMC
March 2016

Application of Multivariate Linear and Nonlinear Calibration and Classification Methods in Drug Design.

Comb Chem High Throughput Screen 2015 ;18(8):795-808

Drug Design in Silico Lab., Chemistry Faculty, University of Tehran, Tehran, Iran.

Data manipulation and maximum efficient extraction of useful information need a range of searching, modeling, mathematical, and statistical approaches. Hence, an adequate multivariate characterization is the first necessary step in investigation and the results are interpreted after multivariate analysis. Multivariate data analysis is capable of not only large dataset management but also interpret them surely and rapidly. Application of chemometrics and cheminformatics methods may be useful for design and discovery of new drug compounds. In this review, we present a variety of information sources on chemometrics, which we consider useful in different fields of drug design. This review describes exploratory analysis (PCA), classification and multivariate calibration (PCR, PLS) methods to data analysis. It summarizes the main facts of linear and nonlinear multivariate data analysis in drug discovery and provides an introduction to manipulation of data in this field. It handles the fundamental aspects of basic concepts of multivariate methods, principles of projections (PCA and PLS) and introduces the popular modeling and classification techniques. Enough theory behind these methods, more particularly concerning the chemometrics tools is included for those with little experience in multivariate data analysis techniques such as PCA, PLS, SIMCA, etc. We describe each method by avoiding unnecessary equations, and details of calculation algorithms. It provides a synopsis of the method followed by cases of applications in drug design (i.e., QSAR) and some of the features for each method.
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http://dx.doi.org/10.2174/1386207318666150803142158DOI Listing
June 2016

Discovery of new potential antimalarial compounds using virtual screening of ZINC database.

Comb Chem High Throughput Screen 2015 ;18(2):227-34

Drug Design in Silico Lab., Chemistry Faculty, K N Toosi University of Technology, Tehran, Iran.

Falcipain-3 (FP-3) is a cysteine protease of the malaria parasite Plasmodium falciparum which is a promising and attractive target enzyme for antiparasitic chemotherapy. In this study, a support vector machine (SVM) model based on fingerprint-based descriptors was developed on a dataset of 239 FP-3 inhibitors to identify the most active antimalarial compounds among the active compounds provided from similarity search. The satisfactory classification performance achieved by the SVM model shows its ability to use it as a further filter to distinguish the most active compounds. The accuracy in prediction for the training, test and external validation sets were 97.39%, 94.74% and 90.6%, respectively. Furthermore, the performance of the model was examined by plotting the receiver operating characteristic (ROC) curve, and the area under the ROC curve was 0.96 for the modeling set. The ability of a virtual screening scheme to scaffold hopping or lead hopping is known as a key ability of an effective method for virtual screening. Three diverse reference FP-3 structures were chosen as active antimalarial compounds to search the lead-like database of ZINC and retrieve the most similar compounds. Compounds having Tanimoto similarity coefficient above 0.8 were extracted for further analysis by classification model. The SVM model rendered five most active compounds and they were also analyzed by ADME/Tox and diversity measures. Maximum property-based distance between extracted compounds was found to be 0.70, which shows the importance of applying multiple diverse reference compounds in the similarity searching.
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http://dx.doi.org/10.2174/1386207318666141229123705DOI Listing
September 2015

Methods and applications of structure based pharmacophores in drug discovery.

Curr Top Med Chem 2013 ;13(9):1036-47

Faculty of Chemistry, KN Toosi University of Technology, Tehran, Iran.

A pharmacophore model does not describe a real molecule or a real association of functional groups but illustrates a molecular recognition of a biological target shared by a group of compounds. Pharmacophores also represent the spatial arrangement of essential interactions in a receptor-binding pocket. Structure based pharmacophores (SBPs) can work both with a free (apo) structure or a macromolecule-ligand complex (holo) structure. The SBP methods that derive pharmacophore from protein-ligand complexes use the potential interactions observed between ligand and protein, whereas, the SBP method that aims to derive pharmacophore from ligand free protein, uses only protein active site information. Therefore SBPs do not encounter to challenging problems such as ligand flexibility, molecular alignment as well as proper selection of training set compounds in ligand based pharmacophore modeling. The current review deals with Hot Spot' analysis of binding site to feature generation, several approaches to feature reduction, and considers shape and excluded volumes to SBP model building. This review continues to represent several applications of SBPs in virtual screening especially in parallel screening approach and multi-target drug design. Also it reports the applications of SBPs in QSAR. This review emphasizes that SBPs are valuable tools for hit to lead optimization, virtual screening, scaffold hopping, and multi-target drug design.
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http://dx.doi.org/10.2174/1568026611313090006DOI Listing
January 2014

Pharmacophore Identification, Molecular Docking, Virtual Screening, and In Silico ADME Studies of Non-Nucleoside Reverse Transcriptase Inhibitors.

Mol Inform 2012 Dec 30;31(11-12):856-66. Epub 2012 Nov 30.

Chemistry Department, Faculty of Sciences, K. N. Toosi University of Technology, Tehran, Iran fax: +98-21-22853650; tel: +98-21-22850266.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique antiviral potency, high specificity and low toxicity in antiretroviral combination therapies used to treat HIV. In this study, chemical feature based pharmacophore models of different classes of NNRT inhibitors of HIV-1 have been developed. The best HypoRefine pharmacophore model, Hypo 1, which has the best correlation coefficient (0.95) and the lowest RMS (0.97), contains two hydrogen bond acceptors, one hydrophobic and one ring aromatic feature, as well as four excluded volumes. Hypo 1 was further validated by test set and Fischer validation method. The best pharmacophore model was then utilized as a 3D search query to perform a virtual screening to retrieve potential inhibitors. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five and docking studies by Libdock and Gold methods to refine the retrieved hits. Finally, 7 top ranked compounds based on Gold score fitness function were subjected to in silico ADME studies to investigate for compliance with the standard ranges.
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http://dx.doi.org/10.1002/minf.201200018DOI Listing
December 2012

3D-QSAR analysis of human immunodeficiency virus entry-1 inhibitors by CoMFA and CoMSIA.

Eur J Med Chem 2010 Nov 10;45(11):4897-903. Epub 2010 Aug 10.

Chemistry Department, Faculty of Sciences, K.N. Toosi University of Technology, Tehran, Iran.

3D-QSAR studies namely CoMFA, CoMFA region focusing and CoMSIA have been carried out on a series (36 compounds) of HIV-1 entry inhibitors. An alignment rule for the compounds was defined using Distill in SYBYL 7.3. Models were validated using a data set obtained by dividing the data set into a training set and test set using hierarchical clustering, based on the CoMFA fields and biological activities (pIC(50)). The best predictions were obtained with a CoMFA region-focusing model (q(2) = 0.719, r(pred)(2) = 0.911), CoMFA standard model (q(2) = 0.660, r(pred)(2) = 0.890), and CoMSIA (steric and hydrophobic) model (q(2) = 0.521, r(pred)(2) = 0.794). The statistical parameters from the models indicate that the data are well fitted and have high predictive ability. Moreover, the resulting 3D CoMFA/CoMSIA contour maps provide useful guidance for designing highly active inhibitors.
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http://dx.doi.org/10.1016/j.ejmech.2010.07.062DOI Listing
November 2010