- De Novo Design of Bioactive Small Molecules by Artificial Intelligence
-
Generative artificial intelligence offers a fresh view on molecular design. We present the first-time prospective application of a deep learning model for designing new druglike compounds with desired activities. For this purpose, we trained a recurrent neural network to capture the constitution of a large set of known bioactive compounds represented as SMILES strings. By transfer learning, this general model was fine-tuned on recognizing retinoid X and peroxisome proliferator-activated receptor agonists. We synthesized five top-ranking compounds designed by the generative model. Four of the compounds revealed nanomolar to low-micromolar receptor modulatory activity in cell-based assays. Apparently, the computational model intrinsically captured relevant chemical and biological knowledge without the need for explicit rules. The results of this study advocate generative artificial intelligence for prospective de novo molecular design, and demonstrate the potential of these methods for future medicinal chemistry.
- Merk, Daniel,Friedrich, Lukas,Grisoni, Francesca,Schneider, Gisbert
-
-
Read Online
- Peptidomimetic analogues of an Arg-Trp-x-x-Trp motif responsible for interaction of translocase MraY with bacteriophage ?X174 lysis protein E
-
Translocase MraY is the target for bacteriophage ?X174 lysis protein E, which interacts via a protein–protein interaction mediated by Phe-288 and Glu-287 of E. coli MraY, and an Arg-Trp-x-x-Trp motif on protein E, also found in several cationic antimicrob
- Kerr, Rachel V.,Fairbairn, Julia A.,Merritt, Andrew T.,Bugg, Timothy D.H.
-
-
- Development of DHQ-based chemical biology probe to profile cellular targets for HBV
-
Chronic hepatitis B virus (HBV) infection has been a serious public health burden worldwide. Current anti-HBV therapies could not eliminate HBV ultimately. Considering the characteristics of HBV, it is impossible to be entirely cured based on current therapies. Therefore, it is urgently needed to develop novel therapeutic agents with new mechanism of action. The dihydroquinolizinone (DHQ) derivatives exhibited potent anti-HBV activity by decreasing HBV DNA and HBsAg level in an obscure mechanism of action. In this study, we have optimized the DHQ scaffold, developed the photoaffinity probe, with which to identify potential binding proteins.
- Zhang, Qing,Huang, Jianzhou,Chow, Hoi Yee,Wang, Jinzheng,Zhang, Yingjun,Fung, Yi Man Eva,Ren, Qingyun,Li, Xuechen
-
supporting information
(2020/10/29)
-
- Synthesis and biological evaluation of novel 5,6,7-trimethoxy flavonoid salicylate derivatives as potential anti-tumor agents
-
5,6,7-Trimethoxy flavonoid salicylate derivatives were designed by the joining of three important pharmacophores (TMP, flavonoid, and SA) according to the combination principle. A series of novel trimethoxy flavonoid salicylate derivatives were synthesized and their in vitro anti-tumor activities were evaluated. Among these derivatives, compound 7f exhibited excellent antiproliferative activity against HGC-27 cells and MGC-803 cells with IC50 values of 10.26 ± 6.94 μM and 17.17 ± 3.03 μM, respectively. Subsequently, the effects on cell colony formation (clonogenic survival assay), cell migration (wound healing assay), cell cycle distribution (PI staining assay), cell apoptosis (Hoechst 33258 staining assay and annexin V-FITC/PI dual staining assay), lactate level (lactate measurement), microtubules disarrangement (immunofluorescence staining analysis) and docking posture (molecular docking simulation) were determined. Further western blot analysis confirmed that compound 7f could effectively down-regulate the expression of glycolysis-related proteins HIF-1α, PFKM and PKM2 and tumor angiogenesis-related proteins VEGF. Overall, these studies suggested that compound 7f, as the representative compound of those, might be a promising candidate for the treatment of gastric cancer and deserved the further studies.
- Deng, Xiangping,Feng, Wanshi,Lei, Xiaoyong,Liu, Renbo,Peng, Yijiao,Tang, Guotao,Xie, Zhizhong,Xiong, Runde,Zheng, Xing,Zou, Yang
-
-
- Preparation method of tricyclic compound drug intermediate for regulating activity of FXR
-
The invention discloses a preparation method of a tricyclic compound drug intermediate for regulating the activity of a Farniol x receptor (FXR). The method comprises the following steps: firstly, esterifying 4-bromosalicylic acid and methanol to obtain 4
- -
-
Paragraph 0034-0036; 0043-0045
(2019/08/01)
-
- PYRROLO [2, 3-B] PYRIDINES OR PYRROLO [2, 3-B] PYRAZINES AS HPK1 INHIBITOR AND THE USE THEREOF
-
Disclosed herein is a compound of Formula (AIII) or (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising thereof. Also disclosed is a method of treating HPK1 related disorders or diseases by using the compound disclosed herein.
- -
-
Paragraph 0401; 2007-2009
(2020/01/08)
-
- Design, synthesis, and preliminary biological evaluation of 3′,4′,5′-trimethoxy flavonoid salicylate derivatives as potential anti-tumor agents
-
According to the pharmacophore combination principle, a set of new 3′,4′,5′-trimethoxy flavonoid salicylate derivatives were designed, synthesized, and evaluated for biological activity. The cytotoxicity evaluation revealed that compound 10v exhibited higher potency than 5-Fu against HCT-116 cells. Preliminary biological activity studies showed that compound 10v could inhibit the colony formation and migration of HCT-116 cells. Besides, the Hoechst 33258 staining assay and flow cytometry revealed that treatment with compound 10v induced the apoptosis of HCT-116 cells in a concentration-dependent manner, while it had no effect on their cell cycle. The WB analysis suggested that HIF-1α, tubulin, HK-2, and PFK might be the potential pharmacophore targets of compound 10v. Tubulin was a potential drug target for compound 10v, which was explained by analyzing the crystal structure of compound 10v complexed with tubulin. These results indicated that compound 10v might be a promising anti-tumor agent candidate, deserving further optimization and evaluation.
- Deng, Xiangping,Liu, Renbo,Li, Junjian,Li, Zhongli,Liu, Juan,Xiong, Runde,Lei, Xiaoyong,Zheng, Xing,Xie, Zhizhong,Tang, Guotao
-
p. 1874 - 1884
(2019/01/28)
-
- Temperature-Controlled Evolution of Nanoporous MOF Crystallites into Hierarchically Porous Superstructures
-
Sophisticated multichannel tubular structures have long been utilized in biological systems. However, the well-controlled assembly of biomimetic materials utilizing these features still remains a challenge. Herein, we report an unexpected one-pot fabrication of biomimetic hierarchically porous metal-organic framework (MOF) tubular superstructures. This temperature-controlled structural evolution was investigated under solvothermal conditions: crystalline hollow MOF tubes can be obtained via self-templating and self-healing at higher temperatures, whereas hierarchical helical or multichannel tubular superstructures are fabricated through a helical or oriented evolution process at lower temperatures. Our work here presents the first example of tubular MOF superstructures and highlights the unexpected power of self-assembly and healing during structural evolution process. It has been widely observed in various scales that complex systems have a hierarchical or multilevel organization. For instance, hierarchical tubular structures are commonly adopted in natural systems, including bears and bamboo, as a result of long-term evolution, which can help enhance fluid transportation in plants, reduce the overall weight of animals, and prevent heat transfer. Our discovery here mimics the natural evolution and generates a series of hierarchically porous metal-organic framework (MOF) superstructures through self-templating, self-healing, and oriented evolution. This facile strategy provides fresh insights into MOF growth and oriented evolution mechanisms, enabling the state-of-the-art design of multichannel materials with promising applications in water harvesting and transport, multicomponent drug delivery, efficient catalysis, and fabrication of multichannel carbon rods for energy storage. Hierarchically porous superstructures have been successfully assembled from nanoporous MOF crystallites. Benefiting from the dynamic coordination bond formation, hierarchical helical or multichannel tubular superstructures can be accessed through oriented assembly of MOF crystallites. This temperature-controlled structural evolution also enables the formation of crystalline hollow MOF tubes via self-templating and self-healing processes. Further incorporation of multiple components into these frameworks provides a fresh route for preparing stable, multivariate, and hierarchical frameworks with accessible catalytically active sites for heterogeneous catalysis.
- Feng, Liang,Li, Jia-Luo,Day, Gregory S.,Lv, Xiu-Liang,Zhou, Hong-Cai
-
supporting information
p. 1265 - 1274
(2019/05/07)
-
- FUSED TRICYCLIC COMPOUNDS AND USES THEREOF IN MEDICINE
-
The present invention relates to a fused tricyclic compound and use thereof as a medicament, in particular as a medicament for the treatment and/or prevention of hepatitis B. Specifically, the invention relates to a compound having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein each variate is as defined in specification. The invention also relates to the use of the compound having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof as a medicament, especially as a medicament for the treatment and/or prevention of hepatitis B.
- -
-
Paragraph 00188
(2019/01/05)
-
- Imidazo[1,2-a]pyridine compound, and preparation method and applications thereof
-
The invention discloses an imidazo[1,2-a]pyridine compound, and a preparation method and applications thereof. The imidazo[1,2-a]pyridine compound can inhibit the activity of NEK2 kinases as an NEK2 micro-molecular inhibitor with a novel structure. The in
- -
-
Paragraph 0068; 0072
(2017/08/28)
-
- 2,3-DIHYDRO-4H-1,3-BENZOXAZIN-4-ONE DERIVATIVES AS MODULATORS OF CHOLINERGIC MUSCARINIC M1 RECEPTOR
-
The present invention provides a compound having a cholinergic muscarinic M1 receptor positive allosteric modulator activity, which may be useful as a prophylactic or therapeutic drug for Alzheimer's disease, schizophrenia, pain, sleep disorder, Parkinson's disease dementia, dementia with Lewy bodies and the like. The present invention relates to a compound represented by the formula (I) or a salt thereof: wherein each symbol is as defined in the attached DESCRIPTION.
- -
-
Paragraph 0458
(2017/01/09)
-
- BICYCLIC [4,6,0] HYDROXAMIC ACIDS AS HDAC INHIBITORS
-
The present invention relates to inhibitors of zinc-dependent histone deacetylases (HDACs) useful in the treatment of diseases or disorders associated with HDAC6, having a Formulae I or Formula II: where R, L, X1, X2, X3,
- -
-
Paragraph 0245; 0246; 0247
(2016/08/29)
-
- BENZOISOXAZOLE-SUBSTITUTED COMPOUNDS AS MGLUR4 ALLOSTERIC POTENTIATORS, COMPOSITIONS, AND METHODS OF TREATING NEUROLOGICAL DYSFUNCTION
-
Compounds which are useful as allosteric potentiators/positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of using the compounds, for example, in treating neurological and psychiatric disorders or other disease state associated with glutamate dysfunction.
- -
-
Page/Page column 76
(2016/08/10)
-
- Chromatography-free, Mitsunobu-triggered heterocyclizations of salicylhydroxamic acids to 3-hydroxybenzisoxazoles
-
The Mitsunobu reaction has become one of the most powerful tools to alkylate acidic pronucleophiles. A significant caveat of Mitsunobu chemistry, however, is that the reaction mixture is often plagued with purification problems owing to the phosphine oxide and hydrazine dicarboxylate by-products. In addition to the development of more readily separable Mitsunobu reagents, the product's physicochemical properties may be exploited to facilitate purification. In this regard, we present a swift and efficient preparation of 3-hydroxybenzisoxazoles by the Mitsunobu-triggered heterocyclizations of salicylhydroxamic acids, which can be isolated by an acid–base work-up. As expected, a range of functional groups was compatible with the chemistry.
- Van Eker, Daniel,Chauhan, Jay,Murphy, William A.,Conlon, Ivie L.,Fletcher, Steven
-
p. 5301 - 5303
(2016/11/16)
-
- ISOINDOLINE-1-ONE DERIVATIVES AS CHOLINERGIC MUSCARINIC M1 RECEPTOR POSITIVE ALLOESTERIC MODULATOR ACTIVITY FOR THE TREATMENT OF ALZHEIMERS DISEASE
-
The present invention provides a compound having a cholinergic muscarinic M1 receptor positive allosteric modulator activity and useful as an agent for the prophylaxis or treatment of Alzheimer's disease, schizophrenia, pain, sleep disorder, Parkinson's disease dementia, dementia with Lewy bodies, and the like. The present invention relates to a compound represented by the formula (I) or a salt thereof. (I) wherein each symbol is as described in the specification, or a salt thereof.
- -
-
Paragraph 0372
(2015/11/10)
-
- Design of potent and selective hybrid inhibitors of the mitotic kinase nek2: Structure-activity relationship, structural biology, and cellular activity
-
We report herein a series of Nek2 inhibitors based on an aminopyridine scaffold. These compounds have been designed by combining key elements of two previously discovered chemical series. Structure based design led to aminopyridine (R)-21, a potent and selective inhibitor able to modulate Nek2 activity in cells.
- Innocenti, Paolo,Cheung, Kwai-Ming J.,Solanki, Savade,Mas-Droux, Corine,Rowan, Fiona,Yeoh, Sharon,Boxall, Kathy,Westlake, Maura,Pickard, Lisa,Hardy, Tara,Baxter, Joanne E.,Aherne, G. Wynne,Bayliss, Richard,Fry, Andrew M.,Hoelder, Swen
-
experimental part
p. 3228 - 3241
(2012/06/01)
-
- 1,3-BENZOTHIAZINONE DERIVATIVES AND USE THEREOF
-
This invention provides a compound represented by the formula (I) :wherein R1 is a hydrogen atom, a halogen atom, hydroxy, nitro, optionally halogenated alkyl, alkoxy optionally having substituents, acyl or amino optionally having substituents;R2 is pyridyl, furyl, thienyl, pyrrolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, tetrahydroquinolyl or thiazolyl, each of which may have substituents;n is 1 or 2; or a salt. And this invention provides a safe pharmaceutical comprising the compound of the formula (I) , which has an excellent apoptosis inhibitory effect and MIF binding effect, for preventing and/or treating heart disease, nervous degenerative disease, cerebrovascular disease, central nervous infectious disease, traumatorathy, demyelinating disease, bone and articular disease, kidney disease, liver disease, osteomyelodysplasia, AIDS, cancer, and the like.
- -
-
-