In silico study on indole derivatives as anti HIV-1 agents: a combined docking, molecular dynamics and 3D-QSAR study

Balupuri, Anand; Gadhe, Changdev G.; Balasubramanian, Pavithra K.; Kothandan, Gugan; Cho, Seung Joo

doi:10.1007/s12272-013-0313-1

Cited by 19 publications

(11 citation statements)

References 31 publications

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“…Then, after the structural-based alignment of CYP11B1 from 4DVQ-A, the initial 3D structure of CYP11B1 was obtained from a homology modeling procedure shown in Figure 5d. Evaluation of the homology models consists of Profiles_3D scores and Ramachandran plot analysis [25] (Figure 5c).…”

Section: Resultsmentioning

confidence: 99%

Combined Pharmacophore Modeling, 3D-QSAR, Homology Modeling and Docking Studies on CYP11B1 Inhibitors

Wang

et al. 2015

Molecules

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Abstract:The mitochondrial cytochrome P450 enzymes inhibitor steroid 11β-hydroxylase (CYP11B1) can decrease the production of cortisol. Therefore, these inhibitors have an effect in the treatment of Cushing's syndrome. A pharmacophore model generated by Genetic Algorithm with Linear Assignment for Hypermolecular Alignment of Datasets (GALAHAD) was used to align the compounds and perform comparative molecular field analysis (CoMFA) with Q 2 = 0.658, R 2 = 0.959. The pharmacophore model contained six hydrophobic regions and one acceptor atom, and electropositive and bulky substituents would be tolerated at the A and B sites, respectively. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study based on the alignment with the atom root mean square (RMS) was applied using comparative molecular field analysis (CoMFA) with Q 2 = 0.666, R 2 = 0.978, and comparative molecular similarity indices analysis (CoMSIA) with Q 2 = 0.721, R 2 = 0.972. These results proved that all the models have good predictability of the bioactivities of inhibitors. Furthermore, the QSAR models indicated that a hydrogen bond acceptor substituent would be disfavored at the A and B groups, OPEN ACCESSMolecules 2015, 20 1015 while hydrophobic groups would be favored at the B site. The three-dimensional (3D) model of the CYP11B1 was generated based on the crystal structure of the CYP11B2 (PDB code 4DVQ). In order to probe the ligand-binding modes, Surflex-dock was employed to dock CYP11B1 inhibitory compounds into the active site of the receptor. The docking result showed that the imidazolidine ring of CYP11B1 inhibitors form H bonds with the amino group of residue Arg155 and Arg519, which suggested that an electronegative substituent at these positions could enhance the activities of compounds. All the models generated by GALAHAD QSAR and Docking methods provide guidance about how to design novel and potential drugs for Cushing's syndrome treatment.

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Section: Resultsmentioning

confidence: 99%

Combined Pharmacophore Modeling, 3D-QSAR, Homology Modeling and Docking Studies on CYP11B1 Inhibitors

Wang

et al. 2015

Molecules

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“…In this approach, lowest energy conformation of the most potent compound 34 derived from systematic conformational search was considered as template for sketching the rest of the molecules. This study can also contribute to the better understanding of binding pose between these inhibitors and gp120 glycoprotein, and provide structural information affecting activity of these inhibitors and improve the understanding of ligandereceptor interactions, resulting in some useful and rational suggestions for further design of novel inhibitors for HIV/AIDS therapy [59].…”

Section: Indole Derivatives As Entry and Fusion Inhibitormentioning

confidence: 99%

A review on recent developments of indole-containing antiviral agents

Zhang

Chen

Yang

2015

European Journal of Medicinal Chemistry

734

215

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Indole represents one of the most important privileged scaffolds in drug discovery. Indole derivatives have the unique property of mimicking the structure of peptides and to bind reversibly to enzymes, which provide tremendous opportunities to discover novel drugs with different modes of action. There are seven indole-containing commercial drugs in the Top-200 Best Selling Drugs by US Retail Sales in 2012. There are also an amazing number of approved indole-containing drugs in the market as well as compounds currently going through different clinical phases or registration statuses. This review focused on the recent development of indole derivatives as antiviral agents with the following objectives: 1) To present one of the most comprehensive listings of indole antiviral agents, drugs on market or compounds in clinical trials; 2) To focus on recent developments of indole compounds (including natural products) and their antiviral activities, summarize the structure property, hoping to inspire new and even more creative approaches; 3) To offer perspectives on how indole scaffolds as a privileged structure might be exploited in the future.

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“…Statistical confidence of the derived model was built by 10cycle boot-strap analysis. Assessment of non-cross validated models was evaluated using correlation co-efficient (r 2 ) and F-value where actual versus predicted pIC 50 values were correlated by linear regression [30]. The calculation of predictive r 2 is done by following Eq.…”

Section: Partial Least Square Regression Analysismentioning

confidence: 99%

New molecular insights into dual inhibitors of tankyrase as Wnt signaling antagonists: 3D-QSAR studies on 4H-1,2,4-triazole derivatives for the design of novel anticancer agents

2020

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Genetic mutations in APC or CNTBB1 gene with aberrant canonical Wnt/β-catenin pathway are responsible for more than 90% of colorectal carcinogenesis. Tankyrases (TNKS) are known to downregulate Wnt signaling by stabilizing AXIN protein through poly(ADP ribose)polymerization or PARSylation process and subsequently, promoting degradation of intracellular β-catenin. Tankyrase enzymes are modulated by a range of known inhibitors that bind individually to any of the nicotinamide or induced adenosine pockets or as dual binding antagonists. Hence, for designing dual tankyrase inhibitors as Wnt signaling antagonist; we carried out 3D-QSAR studies using a data set of 51 molecules of reported 3,4,5-trisubstituted 4H-1,2,4-triazole derivatives. These reported 51 molecules were divided into a training set (39 molecules) and test set (12 molecules), aligned and subjected to generate CoMFA, CoMSIA, and HQSAR models. CoMFA analysis showed q 2 value of 0.694, r 2 ncv value of 0.991 and r 2 pred value of 0.641. Optimized CoMSIA analysis (SEHA) showed q 2 value of 0.624, r 2 ncv value of 0.909 and r 2 pred value of 0.850. Both internal and external validations were performed for generated models of CoMFA and CoMSIA (SEHA) and satisfactory results were obtained. HQSAR analysis showed q 2 , r 2 , and r 2 pred values of 0.781, 0.901, and 0.811, respectively. Applicability domain was also found to be satisfactory with all compounds falling within the range and no outlier was observed. Contour maps from all studies provided significant results with identification of desired spatial arrangement of different atoms or functional groups in a molecule. Triazole ring system-based molecules were reported as potent tankyrase inhibitors. These noteworthy results were employed for the design of different triazole derivatives as potent tankyrase inhibitors, wherein a series of 20 different molecules were designed for evaluation of their potentials as novel tankyrase inhibitors.

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In silico study on indole derivatives as anti HIV-1 agents: a combined docking, molecular dynamics and 3D-QSAR study

Cited by 19 publications

References 31 publications

Combined Pharmacophore Modeling, 3D-QSAR, Homology Modeling and Docking Studies on CYP11B1 Inhibitors

Combined Pharmacophore Modeling, 3D-QSAR, Homology Modeling and Docking Studies on CYP11B1 Inhibitors

A review on recent developments of indole-containing antiviral agents

New molecular insights into dual inhibitors of tankyrase as Wnt signaling antagonists: 3D-QSAR studies on 4H-1,2,4-triazole derivatives for the design of novel anticancer agents

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