循环:一种符合性自编码器,用于有效的异构循环宏观循环骨干采样
Andrew C Powers1, P Douglas Renfrew2, Parisa Hosseinzadeh1
1Department of Bioengineering, University of Oregon, Eugene, Oregon.
bioRxiv : the preprint server for biology
|March 10, 2025
概括
一个新的机器学习模型,CyclicCAE,快速设计能量稳定的宏循环骨干,用于药物发现. 这种方法通过克服异体基质宏循环设计的挑战,加速了新疗法的开发.
科学领域:
- 药用化学 医学化学
- 计算化学的计算化学
- 药物发现 药物发现 药物发现
背景情况:
- 宏观循环代表了一个有前途的治疗类,在药物开发中具有显著的潜力.
- 宏观循环的合理设计受到整合异体和非自然构件的挑战的阻碍.
- 现有的计算方法缺乏针对异体性宏循环设计的具体定制.
研究的目的:
- 开发一种新型的机器学习模型,用于快速生成有利于能源的宏循环骨干.
- 为了解决在异体的宏循环设计和结构预测当前方法的局限性.
- 为加速宏观循环疗法药物设计管道.
主要方法:
- 开发了一个名为CyclicCAE的新型卷积自编码模型.
- 由于数据稀缺,通过内部和in silico方法创建一个定制的宏观循环数据集.
- 对罗塞塔的通用运动循环闭合 (GenKIC) 方法进行循环CAE的基准测试.
主要成果:
- 与GenKIC相比,CyclicCAE在产生能量稳定的宏循环骨干方面表现优越.
- 该模型迅速产生可设计的结构,性能优于最先进的方法.
- 循环CAE提供了能量的最小化,结构生成 (多样化或类似) 和固定元素的inpainting的功能.
结论:
- 循环CAE加速了稳定的宏循环的设计,大大加快了药物发现管道.
- 新型机器学习方法促进了复杂化学构件的整合.
- 这种方法有望推动宏循环药物开发领域的发展.
相关概念视频
02:29Conformations of Cycloalkanes
11.5K
Adolf von Baeyer attempted to explain the instabilities of small and large cycloalkane rings using the concept of angle strain — the strain caused by the deviation of bond angles from the ideal 109.5° tetrahedral value for sp3 hybridized carbons. However, while cyclopropane and cyclobutane are strained, as expected from their highly compressed bond angles, cyclopentane is more strained than predicted, and cyclohexane is virtually strain-free. Hence, Baeyer’s theory that...
11.5K
02:11Conformations of Cyclohexane
12.0K
Cyclohexane does not exist in a planar form due to the high angle and torsional strain it would experience in the planar structure. Instead, it adopts non-planar chair and boat conformations.
The chair form is the most stable and derives its name from its resemblance to the “easy chair.” In the chair conformation, two carbon atoms are arranged out-of-plane — one above and one below, minimizing the torsional strain. In the chair form, the bond angle is very close to the ideal...
The chair form is the most stable and derives its name from its resemblance to the “easy chair.” In the chair conformation, two carbon atoms are arranged out-of-plane — one above and one below, minimizing the torsional strain. In the chair form, the bond angle is very close to the ideal...
12.0K
02:02Chair Conformation of Cyclohexane
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The chair conformation is the most stable form of cyclohexane due to the absence of angle and torsional strain. The absence of angle strain is a result of cyclohexane’s bond angle being very close to the ideal tetrahedral bond angle of 109.5° in its chair conformer. Similarly, the torsional strain is also absent owing to the perfectly staggered arrangement of bonds.
The hydrogen atoms linked to carbons are arranged in two different axial and equatorial orientations to achieve this...
The hydrogen atoms linked to carbons are arranged in two different axial and equatorial orientations to achieve this...
14.2K
02:33Stereoisomerism of Cyclic Compounds
8.6K
In this lesson, we delve into the role of ring conformation and its stability, which determines the spatial arrangement and, consequently, the molecular symmetry and stereoisomerism of cyclic compounds. 1,2-Dimethylcyclohexane is used as a case study to evaluate the possible number of stereoisomers. Here, given the multiple (n = 2) chiral centers, there are 2n = 4 possible configurations that lack a plane of symmetry, as the ring skeleton exists in a non-planar chair conformation. In addition,...
8.6K
02:05Prochirality
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The concept of prochirality leads to the nomenclature of the individual faces of a molecule and plays a crucial role in the enantioselective reaction. It is a concept where two or more achiral molecules react to produce chiral products. A typical process is the reaction of an achiral ketone to generate a chiral alcohol. Here, the achiral reactant reacts with an achiral reducing agent, sodium borohydride, to generate an equimolar mixture of the chiral enantiomers of the product. For example, an...
3.8K
00:52¹H NMR of Conformationally Flexible Molecules: Temporal Resolution
795
At room temperature, the chair conformer of cyclohexane undergoes rapid ring flipping between two equivalent chair conformers at a rate of approximately 105 times per second. These two chair conformers are in equilibrium. The rapid ring flipping results in the interconversion of the axial proton to an equatorial proton and an equatorial to the axial proton. Such interconversions are too rapid and cannot be detected on the NMR timescale. Hence, the NMR spectrometer cannot distinguish between the...
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