The application of in silico drug-likeness predictions in pharmaceutical research

Tian, Sheng; Wang, Junmei; Li, Youyong; Li, Dan; Xu, Lei; Hou, Tingjun

doi:10.1016/j.addr.2015.01.009

Cited by 360 publications

(234 citation statements)

References 92 publications

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“…In silico-design process takes into account parameters such as activity, absorption, distribution, metabolism and excretion and has resulted in a rational drug identification tool [33]. However, in silico-design methods are still computer-based and can’t be directly extrapolated to the efficacy of the compound.…”

Section: Discussionmentioning

confidence: 99%

In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells

2016

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BackgroundComputer-based technology is becoming increasingly essential in biological research where drug discovery programs start with the identification of suitable drug targets. 2-Methoxyestradiol (2ME2) is a 17β-estradiol metabolite that induces apoptosis in various cancer cell lines including cervical cancer, breast cancer and multiple myeloma. Owing to 2ME2’s poor in vivo bioavailability, our laboratory in silico-designed and subsequently synthesized a novel 2ME2 analogue, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol), using receptor- and ligand molecular modeling. In this study, the biological effects of ESE-15-ol (180 nM) and its parent molecule, 2ME2 (1 µM), were assessed on morphology and apoptosis induction in cervical cancer cells.ResultsTransmission electron microscopy, scanning electron microscopy and polarization-optical transmitted light differential interference contrast (PlasDIC) images demonstrated morphological hallmarks of apoptosis including apoptotic bodies, shrunken cells, vacuoles, reduced cell density and cell debris. Flow cytometry analysis showed apoptosis induction by means of annexin V-FITC staining. Cell cycle analysis showed that ESE-15-ol exposure resulted in a statistically significant increase in the G2M phase (72%) compared to 2ME2 (19%). Apoptosis induction was more pronounced when cells were exposed to ESE-15-ol compared to 2ME2. Spectrophotometric analysis of caspase 8 activity demonstrated that 2ME2 and ESE-15-ol both induced caspase 8 activation by 2- and 1.7-fold respectively indicating the induction of the apoptosis. However, ESE-15-ol exerted all of the above-mentioned effects at a much lower pharmacological concentration (180 nM) compared to 2ME2 (1 µM physiological concentration).ConclusionComputer-based technology is essential in drug discovery and together with in vitro studies for the evaluation of these in silico-designed compounds, drug development can be improved to be cost effective and time consuming. This study evaluated the anticancer potential of ESE-15-ol, an in silico-designed compound in vitro. Research demonstrated that ESE-15-ol exerts antiproliferative activity accompanied with apoptosis induction at a nanomolar concentration compared to the micromolar range required by 2ME2. This study is the first study to demonstrate the influence of ESE-15-ol on morphology, cell cycle progression and apoptosis induction in HeLa cells. In silico-design by means of receptor- and ligand molecular modeling is thus effective in improving compound bioavailability while preserving apoptotic activity in vitro.

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Section: Discussionmentioning

confidence: 99%

In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells

2016

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“…The RO5 also rationalizes that molecules having poor absorption are the results of >5HBD, >10HBA, MWT over 500, and log P more than 5. However, there are few existing drugs that violate the RO5 rule and have therapeutic potential [37,38]. 5b showed good drug likeness value (1.22) as compared to 5a (0.83) and ( 5b ) (1.04).…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen–Antioxidant Mutual Prodrugs

Ashraf

Alamgeer

Rasool

et al. 2016

IJMS

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Dexibuprofen–antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5a–c were obtained by reacting its –COOH group with chloroacetyl derivatives 3a–c. The in vitro hydrolysis data confirmed that synthesized prodrugs 5a–c were stable in stomach while undergo significant hydrolysis in 80% human plasma and thus release free dexibuprofen. The minimum reversion was observed at pH 1.2 suggesting that prodrugs are less irritating to stomach than dexibuprofen. The anti-inflammatory activity of 5c (p < 0.001) is more significant than the parent dexibuprofen. The prodrug 5c produced maximum inhibition (42.06%) of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs 5a and 5b showed significant inhibition of pyrexia (p < 0.001). The analgesic activity of 5a is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 5a was more active in decreasing the number of writhes induced by acetic acid than standard dexibuprofen. The ulcerogenic activity results assured that synthesized prodrugs produce less gastrointestinal adverse effects than dexibuprofen. The ex vivo antiplatelet aggregation activity results also confirmed that synthesized prodrugs are less irritant to gastrointestinal mucosa than the parent dexibuprofen. Molecular docking analysis showed that the prodrugs 5a–c interacts with the residues present in active binding sites of target protein. The stability of drug–target complexes is verified by molecular dynamic simulation study. It exhibited that synthesized prodrugs formed stable complexes with the COX-2 protein thus support our wet lab results. It is therefore concluded that the synthesized prodrugs have promising pharmacological activities with reduced gastrointestinal adverse effects than the parent drug.

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“…The oleoyl, palmitoyl and 2-(4-(2-Methylpropyl) phenyl) propanoyl functionalized azaglycine derivatives showed moderate activity (bioactivity scores ranging from-0.23 to-0.3) towards protease and enzyme inhibition properties. The protease inhibition of the derivatives indicates their significance towards antibacterial activity (table 4) [22]. Oral bioavailability and GI absorption of all the derivatives were found to be high except for the oleoyl and the palmitoyl functionalized derivatives which showed low GI absorption.…”

Section: In Silico Molecular Descriptor Studiesmentioning

confidence: 99%

In Silico Studies on Functionalized Azaglycine Derivatives Containing 2, 4-Thiazolidinedione Scaffold on Multiple Targets

Begum

Prasad

et al. 2017

Int J Pharm Pharm Sci

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Objective: The 2, 4-thiazolidinedione containing compounds could lead to most promising scaffolds with higher efficiency toward the targets recognized for its antidiabetic activity when combined with azaglycine moiety. The objective of the present work was to merge functionalized aza glycines with 2, 4-thiazolidinediones, perform in silico evaluation by molecular properties prediction and undertake the molecular docking studies with targets relevant to diabetes, bacterial and viral infections using Swiss Dock programme for unraveling the target identification which can be used for further designing. Methods: (i)In silico studies were performed using Molinspiration online tool, Swiss ADME website and Swiss Target Prediction websites to compute the physicochemical descriptors, oral bioavailability and brain penetration. (ii) Molecular docking studies were performed using Swiss Dock web service for enumeration of binding affinities and assess their biological potentiality. Results:The results predicted good drug likeness, solubility, permeability and oral bioavailability for the compounds. All the compounds showed good docking scores as compared to the reference drugs. The N-oleoyl functionalized aza glycine derivative demonstrated superior binding properties towards all the studied target reference proteins, suggesting its significance in pharmacological actions. Conclusion:The binding interactions observed in the molecular docking studies suggest good binding affinity of the oleoyl functionalized aza glycine derivative, indicating that this derivative would be a promising lead for further investigations of anti-viral, anti-inflammatory and antidiabetic activities.

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The application of in silico drug-likeness predictions in pharmaceutical research

Cited by 360 publications

References 92 publications

In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells

In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells

Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen–Antioxidant Mutual Prodrugs

In Silico Studies on Functionalized Azaglycine Derivatives Containing 2, 4-Thiazolidinedione Scaffold on Multiple Targets

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