In Vitro and In Silico ADME Prediction

Effinger, Angela; O’Driscoll, Caitriona M.; McAllister, Mark; Fotaki, Nikoletta

doi:10.1007/978-3-319-99593-9_13

Cited by 9 publications

(5 citation statements)

References 108 publications

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“…The hit-to-lead phase is a critical phase of all drug-discovery programs, in which a first set of compounds with promising activities against a target is chemically changed into a lead molecule, after an iterative process of structure modification and activity improvement. The aim of this stage is to refine each hit series trying to produce more potent and selective compounds which possess adequate pharmacokinetic (PK) properties [ 31 ]. The experimental determination of PK parameters, an integral component of any small molecule discovery program, is a resource and time-consuming process, that evaluates properties such as absorption, distribution, metabolism and excretion (ADME).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and the In Vitro Evaluation of Antitumor Activity of Novel Thiobenzanilides

et al. 2023

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Cancer is a generic term for a large group of diseases that are the second-leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. Melanoma is a highly aggressive skin tumor with an increasing incidence and poor prognosis in the metastatic stage. Breast cancer still stands as one of the major cancer-associated deaths among women, and diagnosed cases are increasing year after year worldwide. Despite the recent therapeutic advances for this type of cancer, novel drugs and treatment strategies are still urgently needed. In this paper, the synthesis of 18 thiobenzanilide derivatives (17 of them new) is described, and their cytotoxic potential against melanoma cells (A375) and hormone-dependent breast cancer (MCF-7) cells is evaluated using the MTT assay. In the A375 cell line, most of the tested thiobenzanilides derivatives showed EC50 values in the order of μM. Compound 17 was the most promising, with an EC50 (24 h) of 11.8 μM. Compounds 8 and 9 are also interesting compounds that deserve to be further improved. The MCF-7 cell line, on the other hand, was seen to be less susceptible to these thiobenzanilides indicating that these compounds show different selectivity towards skin and breast cancer cells. Compound 15 showed the highest cytotoxic potential for MCF-7 cells, with an EC50 (24 h) of 43 μM, a value within the range of the EC50 value determined for tamoxifen (30.0 μM). ADME predictions confirm the potential of the best compounds. Overall, this work discloses a new set of thiobenzanilides that are worth being considered as new scaffolds for the further development of anticancer agents.

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Section: Resultsmentioning

confidence: 99%

Synthesis and the In Vitro Evaluation of Antitumor Activity of Novel Thiobenzanilides

et al. 2023

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“…Total bile salt concentrations were incorporated in these physiology files based on the values measured in the experimental TIM-1 under fasted and fed state conditions (Figure 1B). 17,18 The different physiology.cat-files were created in Notepad++ and uploaded in GastroPlus using the mixed multiple dosing module (.mdd-file). Table 1 gives an overview of the different.cat-files for the different TIM-1 conditions.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Digitalizing the TIM-1 Model Using Computational Approaches─Part Two: Digital TIM-1 Model in GastroPlus

Hens,

Sarcevica,

Tomaszewska

et al. 2023

Mol. Pharmaceutics

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A TIM-1 model is an in vitro gastrointestinal (GI) simulator considering crucial physiological parameters that will affect the in vivo drug release process. The outcome of these experiments can indicate the critical bioavailability attributes (CBAs) that will impact the fraction absorbed in vivo. The model is widely used in the nonclinical stage of drug product development to assess the bioaccessible fraction of drugs for numerous candidate formulations. In this work, we developed a digital TIM-1 model in the GastroPlus platform. In a first step, we performed validation experiments to assess the luminal concentrations and bioaccessible fractions for two marker compounds. The digital TIM-1 was able to adequately reflect the luminal concentrations and bioaccessible fractions of these markers under different prandial conditions, confirming the appropriate integration of mass transfer in the TIM-1 model. In a second set of experiments, a case example with PF-07059013 was performed, where luminal concentrations and bioaccessible fractions were predicted for 200 and 1000 mg doses under fasted and achlorhydric conditions. Experimental and simulated data pointed out that the achlorhydric effect was more pronounced at the 1000 mg dose, showing a solubility-limited dissolution and, consequently, decreased bioaccessible fraction. Toward future applications, the digital TIM-1 model will be thoroughly applied to explore a link between in vitro and in vivo outcomes based on more case examples with model compounds with the access of TIM-1 and plasma data. Ideally, this digital TIM-1 can be directly used in GastroPlus to explore an in vitro−in vivo correlation (IVIVC) between the fraction dissolved (digital TIM-1 settings) and the fraction absorbed (human PBPK settings).

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“…The accurate computational prediction of pharmacodynamics, ADMET, and pharmaceutical properties for various sets of compounds is currently possible. Such outputs from artificial tools are probably, at least, no worse than those related to the studies in vitro, with several decisive advantages—relatively rapid and dynamic evaluation processes, or the requirement of notably fewer resources [ 127 ], for example.…”

Section: Brief Insight Into Development and Optimization In Drug Disc...mentioning

confidence: 99%

“…The most suitable approach to modern drug design and development is to create a properly balanced set of relevant in silico, in vitro, and in vivo descriptors for the simulation of the pharmacodynamic properties of the drugs and pharmacokinetics in specific human populations, to predict most accurately the interindividual variability [ 127 , 128 ].…”

Section: Brief Insight Into Development and Optimization In Drug Disc...mentioning

confidence: 99%

Research in the Field of Drug Design and Development

Biala,

Kedzierska,

Kruk-Slomka

et al. 2023

Pharmaceuticals

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The processes used by academic and industrial scientists to discover new drugs have recently experienced a true renaissance, with many new and exciting techniques being developed over the past 5–10 years alone. Drug design and discovery, and the search for new safe and well-tolerated compounds, as well as the ineffectiveness of existing therapies, and society’s insufficient knowledge concerning the prophylactics and pharmacotherapy of the most common diseases today, comprise a serious challenge. This can influence not only the quality of human life, but also the health of whole societies, which became evident during the COVID-19 pandemic. In general, the process of drug development consists of three main stages: drug discovery, preclinical development using cell-based and animal models/tests, clinical trials on humans and, finally, forward moving toward the step of obtaining regulatory approval, in order to market the potential drug. In this review, we will attempt to outline the first three most important consecutive phases in drug design and development, based on the experience of three cooperating and complementary academic centers of the Visegrád group; i.e., Medical University of Lublin, Poland, Masaryk University of Brno, Czech Republic, and Comenius University Bratislava, Slovak Republic.

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In Vitro and In Silico ADME Prediction

Cited by 9 publications

References 108 publications

Synthesis and the In Vitro Evaluation of Antitumor Activity of Novel Thiobenzanilides

Synthesis and the In Vitro Evaluation of Antitumor Activity of Novel Thiobenzanilides

Digitalizing the TIM-1 Model Using Computational Approaches─Part Two: Digital TIM-1 Model in GastroPlus

Research in the Field of Drug Design and Development

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