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Article: Design of new molecules against cervical cancer using DFT, theoretical spectroscopy, 2D/3D-QSAR, molecular docking, pharmacophore and ADMET investigations.

El Rhabori, Said / El Aissouq, Abdellah / Daoui, Ossama / Elkhattabi, Souad / Chtita, Samir / Khalil, Fouad

2024 Volume 10, Issue 3, Page(s) e24551

Abstract: Cervical cancer is a major health problem of women. Hormone therapy, via aromatase inhibition, has been proposed as a promising way of blocking estrogen production as well as treating the progression of estrogen-dependent cancer. To overcome the ... ...

Abstract	Cervical cancer is a major health problem of women. Hormone therapy, via aromatase inhibition, has been proposed as a promising way of blocking estrogen production as well as treating the progression of estrogen-dependent cancer. To overcome the challenging complexities of costly drug design, in-silico strategy, integrating Structure-Based Drug Design (SBDD) and Ligand-Based Drug Design (LBDD), was applied to large representative databases of 39 quinazoline and thioquinazolinone compound derivatives. Quantum chemical and physicochemical descriptors have been investigated using density functional theory (DFT) and MM2 force fields, respectively, to develop 2D-QSAR models, while CoMSIA and CoMFA descriptors were used to build 3D-QSAR models. The robustness and predictive power of the reliable models were verified, via several validation methods, leading to the design of 6 new drug-candidates. Afterwards, 2 ligands were carefully selected using virtual screening methods, taking into account the applicability domain, synthetic accessibility, and Lipinski's criteria. Molecular docking and pharmacophore modelling studies were performed to examine potential interactions with aromatase (PDB ID: 3EQM). Finally, the ADMET properties were investigated in order to select potential drug-candidates against cervical cancer for experimental in vitro and in vivo testing.
Language	English
Publishing date	2024-01-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2024.e24551
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Rational identification of small molecules derived from 9,10-dihydrophenanthrene as potential inhibitors of 3CL

Daoui, Ossama / Elkhattabi, Souad / Chtita, Samir

Structural chemistry

2022 Volume 33, Issue 5, Page(s) 1667–1690

Abstract: Small molecules such as 9,10-dihydrophenanthrene derivatives have remarkable activity toward inhibition of SARS-CoV-2 3CL: Supplementary information: The online version contains supplementary material available at 10.1007/s11224-022-02004-z. ...

Abstract	Small molecules such as 9,10-dihydrophenanthrene derivatives have remarkable activity toward inhibition of SARS-CoV-2 3CL Supplementary information: The online version contains supplementary material available at 10.1007/s11224-022-02004-z.
Language	English
Publishing date	2022-07-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2018832-8
ISSN	1572-9001 ; 1040-0400
ISSN (online)	1572-9001
ISSN	1040-0400
DOI	10.1007/s11224-022-02004-z
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Article ; Online: Repositioning Cannabinoids and Terpenes as Novel EGFR-TKIs Candidates for Targeted Therapy Against Cancer: A virtual screening model using CADD and biophysical simulations

Daoui, Ossama / Mali, Suraj N. / Elkhattabi, Kaouakeb / Elkhattabi, Souad / Chtita, Samir

Heliyon. 2023 Apr., v. 9, no. 4 p.e15545-

2023

Abstract: This study examines the potential of Cannabis sativa L. plants to be repurposed as therapeutic agents for cancer treatment through designing of hybrid Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). A set of 50 phytochemicals was ...

Abstract	This study examines the potential of Cannabis sativa L. plants to be repurposed as therapeutic agents for cancer treatment through designing of hybrid Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). A set of 50 phytochemicals was taken from Cannabinoids and Terpenes and subjected for screening using Semi-flexible and Flexible Molecular Docking methods, MM-GBSA free binding energy computations, and pharmacokinetic/pharmacodynamic (ADME-Tox) predictions. Nine promising phytochemicals, Cannabidiolic acid (CBDA), Cannabidiol (CBD), Tetrahydrocannabivarin (THCV), Dronabinol (Δ-9-THC), Delta-8-Tetrahydrocannabinol (Δ-8-THC), Cannabicyclol (CBL), Delta9-tetrahydrocannabinolic acid (THCA), Beta-Caryophyllene (BCP), and Gamma-Elemene (γ-Ele) were identified as potential EGFR-TKIs natural product candidates for cancer therapy. To further validate these findings, a set of Molecular Dynamics simulations were conducted over a 200 ns trajectory. This hybrid early drug discovery screening strategy has the potential to yield a new generation of EGFR-TKIs based on natural cannabis products, suitable for cancer therapy. In addition, the application of this computational strategy in the virtual screening of both natural and synthetic chemical libraries could support the discovery of a wide range of lead drug agents to address numerous diseases.
Keywords	Cannabis sativa ; beta-caryophyllene ; cancer therapy ; cannabidiol ; drugs ; energy ; epidermal growth factor receptors ; molecular dynamics ; pharmacodynamics ; pharmacokinetics ; phytochemicals ; Cannabis sativa L. ; Virtual Screening ; CADD ; Semi-flexible & Flexible Molecular Docking ; MM-GBSA free Binding energy ; The inhibition constant (Ki) ; EGFR-TKIs ; Breast & Lung Cancer ; Cannabinoids & Terpenes
Language	English
Dates of publication	2023-04
Publishing place	Elsevier Ltd
Document type	Article ; Online
Note	Use and reproduction
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2023.e15545
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Article ; Online: Ligand-Based Design of Novel Quinoline Derivatives as Potential Anticancer Agents: An In-Silico Virtual Screening Approach.

Mkhayar, Khaoula / Daoui, Ossama / Haloui, Rachid / Elkhattabi, Kaouakeb / Elabbouchi, Abdelmoula / Chtita, Samir / Samadi, Abdelouahid / Elkhattabi, Souad

Molecules (Basel, Switzerland)

2024 Volume 29, Issue 2

Abstract: In this study, using the Comparative Molecular Field Analysis (CoMFA) approach, the structure-activity relationship of 33 small quinoline-based compounds with biological anti-gastric cancer activity in vitro was analyzed in 3D space. Once the 3D ... ...

Abstract	In this study, using the Comparative Molecular Field Analysis (CoMFA) approach, the structure-activity relationship of 33 small quinoline-based compounds with biological anti-gastric cancer activity in vitro was analyzed in 3D space. Once the 3D geometric and energy structure of the target chemical library has been optimized and their steric and electrostatic molecular field descriptions computed, the ideal 3D-QSAR model is generated and matched using the Partial Least Squares regression (PLS) algorithm. The accuracy, statistical precision, and predictive power of the developed 3D-QSAR model were confirmed by a range of internal and external validations, which were interpreted by robust correlation coefficients (RTrain2=0.931; Qcv2=0.625; RTest2=0.875). After carefully analyzing the contour maps produced by the trained 3D-QSAR model, it was discovered that certain structural characteristics are beneficial for enhancing the anti-gastric cancer properties of Quinoline derivatives. Based on this information, a total of five new quinoline compounds were developed, with their biological activity improved and their drug-like bioavailability measured using POM calculations. To further explore the potential of these compounds, molecular docking and molecular dynamics simulations were performed in an aqueous environment for 100 nanoseconds, specifically targeting serine/threonine protein kinase. Overall, the new findings of this study can serve as a starting point for further experiments with a view to the identification and design of a potential next-generation drug for target therapy against cancer.
MeSH term(s)	Humans ; Ligands ; Molecular Docking Simulation ; Antineoplastic Agents/pharmacology ; Quinolines/pharmacology ; Quantitative Structure-Activity Relationship ; Stomach Neoplasms/drug therapy
Chemical Substances	Ligands ; Antineoplastic Agents ; Quinolines
Language	English
Publishing date	2024-01-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules29020426
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Article ; Online: Design of new small molecules derived from indolin-2-one as potent TRKs inhibitors using a computer-aided drug design approach.

Haloui, Rachid / Mkhayar, Khaoula / Daoui, Ossama / El Khattabi, Kaouakeb / El Abbouchi, Abdelmoula / Chtita, Samir / Elkhattabi, Souad

Journal of biomolecular structure & dynamics

2024 , Page(s) 1–18

Abstract: Tropomyosin receptor kinase (TRKs) enzymes are responsible for cancers associated with the neurotrophic tyrosine kinase receptor gene fusion and are identified as effective targets for anticancer drug discovery. A series of small-molecule indolin-2-one ... ...

Abstract	Tropomyosin receptor kinase (TRKs) enzymes are responsible for cancers associated with the neurotrophic tyrosine kinase receptor gene fusion and are identified as effective targets for anticancer drug discovery. A series of small-molecule indolin-2-one derivatives showed remarkable biological activity against TRKs enzymatic activity. These small molecules could have an excellent profile for pharmaceutical application in the treatment of cancers caused by TRKs activity. The aim of this study is to modify the structure of these molecules to obtain new molecules with improved TRK inhibitory activity and pharmacokinetic properties favorable to the design of new drugs. Based on these series, we carried out a 3D-QSAR study. As a result, robust and reliable CoMFA and CoMSIA models are developed and applied to the design of 11 new molecules. These new molecules have a biological activity superior to the most active molecule in the starting series. The eleven designed molecules are screened using drug-likeness, ADMET proprieties, molecular docking, and MM-GBSA filters. The results of this screening identified the T1, T3, and T4 molecules as the best candidates for strong inhibition of TRKs enzymatic activity. In addition, molecular dynamics simulations are performed for TRK free and complexed with ligands T1, T3, and T4 to evaluate the stability of ligand-protein complexes over the simulation time. On the other hand, we proposed experimental synthesis routes for these newly designed molecules. Finally, the designed molecules T1, T2, and T3 have great potential to become reliable candidates for the conception of new drug inhibitors of TRKs.Communicated by Ramaswamy H. Sarma.
Language	English
Publishing date	2024-01-13
Publishing country	England
Document type	Journal Article
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2024.2302944
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Article: Repositioning Cannabinoids and Terpenes as Novel EGFR-TKIs Candidates for Targeted Therapy Against Cancer: A virtual screening model using CADD and biophysical simulations.

Daoui, Ossama / Mali, Suraj N / Elkhattabi, Kaouakeb / Elkhattabi, Souad / Chtita, Samir

Heliyon

2023 Volume 9, Issue 4, Page(s) e15545

Abstract: This study examines the potential ... ...

Abstract	This study examines the potential of
Language	English
Publishing date	2023-04-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2023.e15545
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Article ; Online: Combined computational approaches for developing new anti-Alzheimer drug candidates: 3D-QSAR, molecular docking and molecular dynamics studies of liquiritigenin derivatives

Nour, Hassan / Daoui, Ossama / Abchir, Oussama / ElKhattabi, Souad / Belaidi, Salah / Chtita, Samir

Heliyon. 2022 Dec., v. 8, no. 12 p.e11991-

2022

Abstract: Butyrylcholinesterase is an acetylcholine-degrading enzyme involved in the memorization process, which is becoming an interesting target for the symptomatic treatment of Alzheimer's disease. In the present investigation, the structure–activity ... ...

Abstract	Butyrylcholinesterase is an acetylcholine-degrading enzyme involved in the memorization process, which is becoming an interesting target for the symptomatic treatment of Alzheimer's disease. In the present investigation, the structure–activity relationship of a set of Liquiritigenin derivatives recently revealed to be Butyrylcholinesterase inhibitors was studied basing on comparative field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMISA). As a result, performant models with high predictive capability have been developed (CoMFA model: R² = 0.91, Q² = 0.62, R²ₚᵣₑd = 0.85; CoMISA model: R² = 0.92, Q² = 0.59, R²ₚᵣₑd = 0.83) and implemented to design new Liquiritigenin derivatives with improved activity. Besides, the affinity of the designed derivatives towards the active site of Butyrylcholinesterase, was confirmed by molecular docking and molecular dynamics studies. Moreover, they exhibited good pharmacokinetics properties. Accordingly, the outcomes of the present investigations can provide important direction for the development of new anti-Alzheimer's drug candidates.
Keywords	Alzheimer disease ; active sites ; cholinesterase ; drugs ; models ; molecular dynamics ; pharmacokinetics ; structure-activity relationships ; Alzheimer's disease ; Butyrylcholinesterase ; Liquiritigenin ; CoMFA ; CoMISA ; Molecular docking
Language	English
Dates of publication	2022-12
Publishing place	Elsevier Ltd
Document type	Article ; Online
Note	Use and reproduction
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2022.e11991
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Article ; Online: Pharmacophore-based virtual screening, molecular docking, and molecular dynamics studies for the discovery of novel FLT3 inhibitors.

Ouassaf, Mebarka / Daoui, Ossama / Alam, Sarfaraz / Elkhattabi, Souad / Belaidi, Salah / Chtita, Samir

Journal of biomolecular structure & dynamics

2022 Volume 41, Issue 16, Page(s) 7712–7724

Abstract: FLT3 is considered a potential target of acute myeloid leukemia therapy. In this study, we applied a computer-aided methodology unifying molecular docking and pharmacophore screening to identify potent inhibitors against FLT3. To investigate the ... ...

Abstract	FLT3 is considered a potential target of acute myeloid leukemia therapy. In this study, we applied a computer-aided methodology unifying molecular docking and pharmacophore screening to identify potent inhibitors against FLT3. To investigate the pharmacophore area and binding mechanism of FLT3, the reported co-crystallized Gilteritinib ligand was docked into the active site using Glide XP. Based on the docking results, we identified structure-based pharmacophore characteristics resistant to potent FLT3 inhibitors. The best hypothesis was corroborated using test and decoy sets, and the verified hypo was utilized to screen the chemical database. The hits from the pharmacophore-based screening were then screened again using a structure-based method that included molecular docking at various precisions; the selected molecules were further examined and refined using drug-like filters and ADMET analysis. Finally, two hits were picked out for molecular dynamic simulation. The results showed two hits were expected to have potent inhibitory activity and excellent ADMET characteristics, and they might be used as new leads in the development of FLT3 inhibitors.Communicated by Ramaswamy H. Sarma.
Language	English
Publishing date	2022-09-15
Publishing country	England
Document type	Journal Article
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2022.2123403
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Article ; Online: A computer-aided drug design approach to explore novel type II inhibitors of c-Met receptor tyrosine kinase for cancer therapy: QSAR, molecular docking, ADMET and molecular dynamics simulations.

Daoui, Ossama / Nour, Hassan / Abchir, Oussama / Elkhattabi, Souad / Bakhouch, Mohamed / Chtita, Samir

Journal of biomolecular structure & dynamics

2022 Volume 41, Issue 16, Page(s) 7768–7785

Abstract: Small molecules such as 4-phenoxypyridine derivatives have remarkable inhibitory activity against c-Met enzymatic activity and proliferation of cancer cell lines. Since there is a relationship between structure and biological activity of these molecules, ...

Abstract	Small molecules such as 4-phenoxypyridine derivatives have remarkable inhibitory activity against c-Met enzymatic activity and proliferation of cancer cell lines. Since there is a relationship between structure and biological activity of these molecules, these little compounds may have great potential for clinical pharmaceutical use against various types of cancer caused by c-Met activity. The purpose of this study was to remodel the structures of 4-phenoxypyridine derivatives to achieve strong inhibitory activity against c-Met and provide favorable pharmacokinetic properties for drug design and discovery. Therefore, this paper describes the structure-activity relationship and the rationalization of appropriate pharmacophore sites to improve the biological activity of the investigated molecules, based on bioinformatics techniques represented by a computer-aided drug design approach. Accordingly, robust and reliable 3D-QSAR models were developed based on CoMFA and CoMSIA techniques. As a result, 46 lead molecules were designed and their biological and pharmacokinetic activities were predicted in silico. Screening filters by 3D-QSAR, Molecular Docking, drug-like and ADME-Tox identified the computer-designed compounds P54 and P55 as the best candidates to achieve high inhibition of c-Met enzymatic activity compared to the synthesized template compound T14. Finally, through molecular dynamics simulations, the structural properties and dynamics of c-Met free and complex (PDB code: 3LQ8) in the presence of 4-phenoxypyridine-derived compounds in an aqueous environment are discussed. Overall, the rectosynthesis of the designed drug inhibitors (P54 and P55) and their in vitro and in vivo bioactivity evaluation may be attractive for design and discovery of novel drug effective to inhibit c-Met enzymatic activity.Communicated by Ramaswamy H. Sarma.
Language	English
Publishing date	2022-09-19
Publishing country	England
Document type	Journal Article
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2022.2124456
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Zs.A 2093: Show issues

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Article ; Online: Cyclohexane-1,3-dione Derivatives as Future Therapeutic Agents for NSCLC: QSAR Modeling, In Silico ADME-Tox Properties, and Structure-Based Drug Designing Approach.

Daoui, Ossama / Elkhattabi, Souad / Bakhouch, Mohamed / Belaidi, Salah / Bhandare, Richie R / Shaik, Afzal B / Mali, Suraj N / Chtita, Samir

ACS omega

2023 Volume 8, Issue 4, Page(s) 4294–4319

Abstract: The abnormal expression of the c-Met tyrosine kinase has been linked to the proliferation of several human cancer cell lines, including non-small-cell lung cancer (NSCLC). In this context, the identification of new c-Met inhibitors based on heterocyclic ... ...

Abstract	The abnormal expression of the c-Met tyrosine kinase has been linked to the proliferation of several human cancer cell lines, including non-small-cell lung cancer (NSCLC). In this context, the identification of new c-Met inhibitors based on heterocyclic small molecules could pave the way for the development of a new cancer therapeutic pathway. Using multiple linear regression (MLR)-quantitative structure-activity relationship (QSAR) and artificial neural network (ANN)-QSAR modeling techniques, we look at the quantitative relationship between the biological inhibitory activity of 40 small molecules derived from cyclohexane-1,3-dione and their topological, physicochemical, and electronic properties against NSCLC cells. In this regard, screening methods based on QSAR modeling with density-functional theory (DFT) computations, in silico pharmacokinetic/pharmacodynamic (ADME-Tox) modeling, and molecular docking with molecular electrostatic potential (MEP) and molecular mechanics-generalized Born surface area (MM-GBSA) computations were used. Using physicochemical (stretch-bend, hydrogen bond acceptor, Connolly molecular area, polar surface area, total connectivity) and electronic (total energy, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels) molecular descriptors, compound
Language	English
Publishing date	2023-01-19
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.2c07585
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