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
chun发布了新的文献求助10
刚刚
YI应助南兮采纳,获得10
刚刚
orixero应助颜云尔采纳,获得10
1秒前
anna发布了新的文献求助10
1秒前
YWang发布了新的文献求助10
4秒前
4秒前
NiNi完成签到,获得积分10
6秒前
悦耳寒松发布了新的文献求助10
6秒前
sijing发布了新的文献求助10
7秒前
7777完成签到,获得积分10
7秒前
求求了,让孩子毕业吧完成签到,获得积分10
8秒前
8秒前
11秒前
我是老大应助LiuJinhui采纳,获得10
12秒前
15秒前
量子星尘发布了新的文献求助10
15秒前
清久完成签到,获得积分10
16秒前
牛马码字员完成签到,获得积分10
16秒前
橙果果发布了新的文献求助20
17秒前
所所应助11采纳,获得10
17秒前
tt大耳朵完成签到,获得积分10
18秒前
18秒前
19秒前
枫之林发布了新的文献求助10
19秒前
辛俊辰发布了新的文献求助10
19秒前
xiao完成签到 ,获得积分10
19秒前
lemongulf完成签到 ,获得积分10
20秒前
发表多篇高ifsci的第一作者完成签到,获得积分20
21秒前
阅遍SCI完成签到,获得积分10
21秒前
22秒前
飞鱼z完成签到,获得积分10
23秒前
LiuJinhui发布了新的文献求助10
23秒前
Infinit发布了新的文献求助10
25秒前
25秒前
25秒前
悦耳寒松完成签到,获得积分10
26秒前
chun完成签到,获得积分10
28秒前
干煸鸡完成签到,获得积分10
31秒前
31秒前
可爱的函函应助ah爱科研采纳,获得10
32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
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
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
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 3989069
求助须知:如何正确求助?哪些是违规求助? 3531351
关于积分的说明 11253589
捐赠科研通 3269939
什么是DOI,文献DOI怎么找? 1804851
邀请新用户注册赠送积分活动 882074
科研通“疑难数据库(出版商)”最低求助积分说明 809073