Computational planning of the synthesis of complex natural products

Training algorithms to computationally plan multistep organic syntheses has been a challenge for more than 50 years(1-7). However, the field has progressed greatly since the development of early programs such as LHASA(1,7), for which reaction choices at each step were made by human operators. Multiple software platforms(6,8-14) are now capable of completely autonomous planning. But these programs 'think' only one step at a time and have so far been limited to relatively simple targets, the syntheses of which could arguably be designed by human chemists within minutes, without the help of a computer. Furthermore, no algorithm has yet been able to design plausible routes to complex natural products, for which much more far-sighted, multistep planning is necessary(15,16) and closely related literature precedents cannot be relied on. Here we demonstrate that such computational synthesis planning is possible, provided that the program's knowledge of organic chemistry and data-based artificial intelligence routines are augmented with causal relationships(17,18), allowing it to 'strategize' over multiple synthetic steps. Using a Turing-like test administered to synthesis experts, we show that the routes designed by such a program are largely indistinguishable from those designed by humans. We also successfully validated three computer-designed syntheses of natural products in the laboratory. Taken together, these results indicate that expert-level automated synthetic planning is feasible, pending continued improvements to the reaction knowledge base and further code optimization. A synthetic route-planning algorithm, augmented with causal relationships that allow it to strategize over multiple steps, can design complex natural-product syntheses that are indistinguishable from those designed by human experts

Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development

Algorithmic Discovery of Tactical Combinations for Advanced Organic Syntheses

Whereas most organic molecules can be synthesized from progressively simpler substrates, syntheses of complex organic targets often involve counterintuitive sequence of steps that first complexify the structure but, by doing so, open up possibilities for pronounced structural simplification in subsequent, downstream steps. Such complexifying/simplifying reaction sequences, called tactical combinations (TCs), can be quite powerful and elegant but also inherently hard to spot-indeed, only some 500 TCs have so far been cataloged, and even fewer are routinely used in synthetic practice. This paper describes computer-driven discovery of large numbers of viable TCs (over 46,000 combinations of reaction classes and similar to 4.85 million combinations of reaction variants), the vast majority of which have no prior literature precedent. Examples-including a concise wet lab synthesis of a small natural product-are provided to illustrate how the use of these newly discovered TCs can streamline the design of syntheses leading to important drugs and/or natural products

Chematica: A Story of Computer Code That Started to Think like a Chemist

In this Backstory, Bartosz Grzybowski and co-workers narrate their long, long route to a computer program that, as described in more technical terms in their research article in this issue of Chem, is finally capable of autonomous planning of synthetic routes that are subsequently proven to work in the laboratory

Proton FLASH Irradiation Setup for Preclinical Studies at HZB

The HZB cyclotron continues to provide protons for eye tumor treatment in collaboration with the Charit Universitätsmedizin Berlin after 24 years and more than 4400 patients so far. With the perspective of broadening its research capabilities in the field of radiation therapy, intensive effort has been dedicated towards proton FLASH irradiation, which requires ultra high dose rates or beam intensities. By combining a fast and reliable switch off mechanism, accurate dosimetry, and a double scattering beam nozzle with a static 3D printed range modulator, HZB is now able to deliver a dose rate above 150 Gy s within a flat circular irradiation field of 18 mm diameter and a 27 mm spread out Bragg peak with a distal fall off of 1 mm in water. The reproducibility of the delivered dose meets the clinical acceptance criteria for a total irradiation time as low as 2.5 ms. The first experiments with this setup were used on fibroblastic and sarcoma organoids. By adapting the design to a 35 mm lateral field and using optimal accelerator tuning to increase beam transmission, similar or even higher dose rates are expected, satisfying thus the FLASH conditions for eye tumor treatment with proton

Computer-Assisted Planning of Hydroxychloroquine’s Syntheses Commencing from Inexpensive Substrates and Bypassing Patented Routes.

A computer program for retrosynthetic planning helps develop multiple "synthetic contingency" plans for hydroxychloroquine, a promising but yet unproven medication against COVID-19. These plans are designed to navigate, as much as possible, around known and patented routes and to commence from inexpensive and diverse starting materials, such as to ensure supply in case of anticipated market shortages of the commonly used substrates