Shape-Based Virtual Screening of a Billion-Compound Library Identifies Mycobacterial Lipoamide Dehydrogenase Inhibitors

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Bio & Med Chem Au Pub Date : 2023-09-08 DOI:10.1021/acsbiomedchemau.3c00046
Mayako Michino*, Alexandre Beautrait, Nicholas A. Boyles, Aparna Nadupalli, Alexey Dementiev, Shan Sun, John Ginn, Leigh Baxt, Robert Suto, Ruslana Bryk, Steven V. Jerome, David J. Huggins* and Jeremie Vendome*, 
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Abstract

Lpd (lipoamide dehydrogenase) in Mycobacterium tuberculosis (Mtb) is required for virulence and is a genetically validated tuberculosis (TB) target. Numerous screens have been performed over the last decade, yet only two inhibitor series have been identified. Recent advances in large-scale virtual screening methods combined with make-on-demand compound libraries have shown the potential for finding novel hits. In this study, the Enamine REAL library consisting of ∼1.12 billion compounds was efficiently screened using the GPU Shape screen method against Mtb Lpd to find additional chemical matter that would expand on the known sulfonamide inhibitor series. We identified six new inhibitors with IC50 in the range of 5–100 μM. While these compounds remained chemically close to the already known sulfonamide series inhibitors, some diversity was found in the cores of the hits. The two most potent hits were further validated by one-step potency optimization to submicromolar levels. The co-crystal structure of optimized analogue TDI-13537 provided new insights into the potency determinants of the series.

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基于形状的十亿化合物库虚拟筛选确定了分枝杆菌脂酰胺脱氢酶抑制剂
结核分枝杆菌(Mtb)中的 Lpd(脂酰胺脱氢酶)是致病力所必需的,也是经基因验证的结核病(TB)靶标。在过去十年中进行了大量筛选,但只发现了两个抑制剂系列。最近,大规模虚拟筛选方法与按需制造化合物库的结合显示了发现新靶点的潜力。在本研究中,我们使用 GPU Shape 筛选法对由 11.2 亿个化合物组成的 Enamine REAL 库针对 Mtb Lpd 进行了高效筛选,以找到更多的化学物质来扩展已知的磺胺类抑制剂系列。我们发现了六种新的抑制剂,其 IC50 在 5-100 μM 之间。虽然这些化合物在化学性质上与已知的磺酰胺系列抑制剂非常接近,但在新发现的核心化合物中发现了一些多样性。通过一步药效优化至亚摩尔水平,进一步验证了两个药效最强的化合物。优化类似物 TDI-13537 的共晶体结构为了解该系列抑制剂的效力决定因素提供了新的视角。
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ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
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0.00%
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0
期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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