已入深夜,您辛苦了!由于当前在线用户较少,发布求助请尽量完整地填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!祝你早点完成任务,早点休息,好梦!

In Silico and in Vitro Assessment of OATP1B1 Inhibition in Drug Discovery

生物信息学 药物发现 体外 药理学 药品 计算生物学 化学 生物 生物化学 基因
作者
Matthew L. Danielson,Geri A. Sawada,Thomas J. Raub,Prashant Desai
出处
期刊:Molecular Pharmaceutics [American Chemical Society]
卷期号:15 (8): 3060-3068 被引量:14
标识
DOI:10.1021/acs.molpharmaceut.8b00168
摘要

The organic anion-transporting polypeptide 1B1 transporter belongs to the solute carrier superfamily and is highly expressed at the basolateral membrane of hepatocytes. Several clinical studies show drug–drug interactions involving OATP1B1, thereby prompting the International Transporter Consortium to label OATP1B1 as a critical transporter that can influence a compound's disposition. To examine OATP1B1 inhibition early in the drug discovery process, we established a medium-throughput concentration-dependent OATP1B1 assay. To create an in silico OATP1B1 inhibition model, deliberate in vitro assay enrichment was performed with publically known OATP1B1 inhibitors, noninhibitors, and compounds from our own internal chemistry. To date, approximately 1200 compounds have been tested in the assay with 60:40 distribution between noninhibitors and inhibitors. Bagging, random forest, and support vector machine fingerprint (SVM-FP) quantitative structure–activity relationship classification models were created, and each method showed positive and negative predictive values >90%, sensitivity >80%, specificity >95%, and Matthews correlation coefficient >0.8 on a prospective test set indicating the ability to distinguish inhibitors from noninhibitors. A SVMF-FP regression model was also created that showed an R2 of 0.39, Spearman's rho equal to 0.76, and was capable of predicting 69% of the prospective test set within the experimental variability of the assay (3-fold). In addition to the in silico quantitative structure–activity relationship (QSAR) models, physicochemical trends were examined to provide structure activity relationship guidance to early discovery teams. A JMP partition tree analysis showed that among the compounds with calculated logP >3.5 and ≥1 negatively charged atom, 94% were identified as OATP1B1 inhibitors. The combination of the physicochemical trends along with an in silico QSAR model provides discovery project teams a valuable tool to identify and address drug–drug interaction liability due to OATP1B1 inhibition.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
nater2ver完成签到,获得积分10
1秒前
哦哦哦完成签到 ,获得积分10
2秒前
2秒前
Nowind发布了新的文献求助10
2秒前
Vicky完成签到 ,获得积分10
3秒前
Noah完成签到 ,获得积分0
3秒前
葡萄味的果茶完成签到 ,获得积分10
4秒前
王者归来完成签到,获得积分10
4秒前
5秒前
我真的要好好学习完成签到 ,获得积分10
5秒前
evans完成签到,获得积分10
5秒前
别当真完成签到 ,获得积分10
7秒前
xiaomu发布了新的文献求助10
9秒前
小v完成签到 ,获得积分10
9秒前
lijianguo完成签到,获得积分10
9秒前
宇称yu完成签到 ,获得积分10
10秒前
无心的哑铃完成签到 ,获得积分10
11秒前
11秒前
围炉夜话完成签到,获得积分10
11秒前
andrele完成签到,获得积分10
11秒前
12秒前
归尘完成签到,获得积分10
12秒前
Chen完成签到 ,获得积分10
12秒前
乐观寄真完成签到 ,获得积分10
13秒前
Nowind完成签到,获得积分10
13秒前
14秒前
14秒前
钱小豪发布了新的文献求助10
15秒前
Nakacoke77完成签到,获得积分10
16秒前
大可完成签到 ,获得积分10
17秒前
yan完成签到 ,获得积分10
17秒前
归尘发布了新的文献求助10
18秒前
复杂的可乐完成签到 ,获得积分10
18秒前
123zyx完成签到 ,获得积分10
18秒前
黎乐荷发布了新的文献求助10
19秒前
xingxing完成签到 ,获得积分10
19秒前
zhaoxi完成签到 ,获得积分10
20秒前
20秒前
霸气小蜜蜂完成签到 ,获得积分10
20秒前
Jyy77完成签到 ,获得积分10
21秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
Aktuelle Entwicklungen in der linguistischen Forschung 300
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989949
求助须知:如何正确求助?哪些是违规求助? 3532017
关于积分的说明 11255865
捐赠科研通 3270829
什么是DOI,文献DOI怎么找? 1805053
邀请新用户注册赠送积分活动 882233
科研通“疑难数据库(出版商)”最低求助积分说明 809216

今日热心研友

fanyueyue
6
热心市民小红花
10
酷炫的一笑
1
momo
1
孙燕
1
注:热心度 = 本日应助数 + 本日被采纳获取积分÷10