Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics

Smith, Dennis A.; Jones, Barry; Walker, Don K.

doi:10.1002/(sici)1098-1128(199605)16:3<243::aid-med2>3.0.co;2-z

Cited by 228 publications

(153 citation statements)

References 5 publications

(6 reference statements)

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“…All the other compounds, including lead compound 1 will eliminate partially via renal and the faecal route due to molecular weight range from 250-350 Da (Ghibellini et al 2006). Similarly, the highest log D value possessed by the lead compound 1 > 8 > 6 >13 also conferred them to be released metabolically via bile canaliculi and faecal route (Smith et al 1996). Fosmidomycin will be released solely by the renal clearance due to MW less than 250 Da (Na-Bangchang et al 2007).…”

Section: Computational Pharmacokinetic Studiesmentioning

confidence: 99%

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

Wadood

Ghufran

Hassan

et al. 2016

Pharmaceutical Biology

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Fosmidomycin is a promising DXR inhibitor, which showed safety as well as efficacy against Plasmodium falciparum malaria in clinical trials. However, due to its poor oral bioavailability and non-drug-like properties, the focus of medicinal chemists is to develop inhibitors with improved pharmacological properties. Objective: This study described the computational design of new and potent inhibitors for deoxyxylulose 5-phosphate reductoisomerase and the prediction of their pharmacokinetic and pharmacodynamic properties. Material and methods: A complex-based pharmacophore model was generated from the complex X-ray crystallographic structure of PfDXR using MOE (Molecular Operating Environment). Furthermore, MOE-Dock was used as docking software to predict the binding modes of hits and target enzyme.Results: Finally, 14 compounds were selected as new and potent inhibitors of PfDXR on the basis of pharmacophore mapping, docking score, binding energy and binding interactions with the active site residues of the target protein. The predicted pharmacokinetic properties showed improved permeability by efficiently crossing blood-brain barrier. While, in silico promiscuity binding data revealed that these hits also have the ability to bind with other P. falciparum drug targets. Discussion and conclusion: In conclusion, innovative scaffolds with novel modes of action, improved efficacy and acceptable physiochemical/pharmacokinetic properties were computationally identified.ARTICLE HISTORY

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Section: Computational Pharmacokinetic Studiesmentioning

confidence: 99%

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

Wadood

Ghufran

Hassan

et al. 2016

Pharmaceutical Biology

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“…6 Many studies have identified inappropriate pharmacokinetics as the major cause for the failure of a drug development. Appropriate consideration regarding the safety and efficacy of a drug requires an analysis of the links between systemic exposure and effects of the drug.…”

Section: 23mentioning

confidence: 99%

“…4,5 The absorption, distribution, metabolism and elimination of drugs are highly related to human physiological mechanisms. 6 From the reviewed literature, it was found that no study was conducted in Bangladesh on these aspects. This observation has led to an increased emphasis on the pharmacokinetics of pioglitazone under the indigenous conditions of Bangladesh.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics study of Pioglitazone (30 mg) tablets in healthy volunteers

Saha

Chowdhury

Bachar

2015

Dhaka Univ. J. Pharm. Sci

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Pioglitazone, an excellent insulin sensitizer, is used for the treatment of type 2 diabetes mellitus (T2DM). The present investigation demonstrated a single dose pharmacokinetic study of pioglitazone tablet in 24 healthy male volunteers in a randomized protocol. Blood samples were collected before and 0.5 to 24.0 h after a single oral dose of a 30 mg pioglitazone tablet. Plasma pioglitazone level was determined using a validated method of reversed phase binary high performance liquid chromatography (HPLC). The pharmacokinetic parameters determined were 1.117 ± 0.315 (µg/ml), 2.5 ± 0.735 (h), 9.014 ± 3.385 (µg.h/ml), 8.081 ± 3.407 (µg. h/ml), 1.315 ± 0.964 (h), 0.707 ± 1.636 (h -1 ), 0.078 ± 0.02 (h -1 ) and 8.884 ± 03.808 (h) for Cmax, Tmax, AUC0-∞, AUC0-24, Ka, T1/2 (α), Kel, and T1/2(β), respectively. Variation of pioglitazone pharmacokinetic parameters in Bangladeshi population compared to Chinese, Thai and German population may indicate the polymorphic variation in the pioglitazone responsive metabolizing gene CYP3A4 and CYP2C19 in our population.

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“…Coefficient are widely used to make estimates for membrane penetration and permeability, including gastrointestinal absorption [41,42], blood-brain barrier (BBB) crossing [43,44], and correlations to pharmacokinetic properties [45].…”

Section: Octanol/water Partition Log Pmentioning

confidence: 99%

Conformational Analysis, Substituent Effect and Structure Activity Relationships of 16-Membered Macrodiolides

Mazri

Belaidi

Kerassa

et al. 2014

ILCPA

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Electronic structures, Conformational Analysis, effect of the substitution and structure activity Relationships for macrodiolides, have been studied by PM3 and ab initio methods. In the present work, the calculated values, namely net charges, bond lengths, MESP, dipole moments, electronaffinities, heats of formation, drug-likeness and QSAR properties, are reported and discussed in terms of the biological activity of macrodiolides.

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Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics

Cited by 228 publications

References 5 publications

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

Pharmacokinetics study of Pioglitazone (30 mg) tablets in healthy volunteers

Conformational Analysis, Substituent Effect and Structure Activity Relationships of 16-Membered Macrodiolides

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