KRAS-G12D mutations are the one of most frequent oncogenic drivers in human cancers. Unfortunately, no therapeutic agent directly targeting has been clinically approved yet, with such mutated species remaining undrugged. Notably, cofactor Mg2+ is closely related to function small GTPases, but investigation conducted yet on when associated KRAS. Herein, through microsecond scale molecular dynamics simulations, we found that plays a crucial role conformational changes KRAS-GDP complex. We...

The NRAS-mutant subset of melanoma represent some the most aggressive and deadliest types associated with poor overall survival. Unfortunately, for more than 40 years, no therapeutic agent directly targeting NRAS mutations has been clinically approved. In this work, based on microsecond scale molecular dynamics simulations, effect Q61 conformational characteristics is revealed at atomic level. GTP-bound NRAS-Q61R Q61K show a specific targetable pocket between Switch-II α-helix 3 whereas...

A novel methodology for the annulation of terminal alkynes and o-phenylenediamines by using a combination cobalt catalyst oxygen as oxidant is reported. This method shows wide substrate scope good functional group tolerance provides range quinoxalines in to high yields. The demonstrated its gram-scale broad potential applications. Furthermore, this protocol serves powerful tool late-stage functionalization various complex bioactive molecules drugs provide new class containing two distinct...

KRAS oncogenes are the largest family of mutated RAS isoforms, participating in about 30% all cancers. Due to their paramount medical importance, enormous effort is being devoted development inhibitors using clinical tests, wet-lab experiments and drug design, this a preliminary step process creating new drugs, prior synthesis testing. One central aspect drugs characterisation species that can be used for treatment. In aim, we propose computational framework based on combined all-atom...

Abstract Cyclic diguanosine monophosphate (c-di-GMP) is a ubiquitous bacterial secondary messenger with diverse functions. A previous Escherichia coli proteome microarray identified that c-di-GMP binds to the 23S rRNA methyltransferases RlmI and RlmE. Here we show inhibits activity in methylation assays, it modulates ribosome assembly presence of kanamycin. Molecular dynamics simulation mutagenesis studies reveal at residues R64, R103, G114, K201. Structural simulations indicate quenches by...

The use of drugs derived from benzothiadiazine, a bicyclic heterocyclic benzene derivative, has become widespread treatment for diseases such as hypertension, low blood sugar or the human immunodeficiency virus, among others. In this work we have investigated interactions benzothiadiazine and four its derivatives designed in silico with model zwitterionic cell membranes formed by dioleoylphosphatidylcholine, 1,2-dioleoyl-sn-glycero-3-phosphoserine cholesterol at liquid-crystal phase inside...

A controllable palladium-catalyzed intramolecular C-H activation of N-alkyl- N-arylanthranilic acids has been developed. The methodology allows selective synthesis 1,2-dihydro-(4 H)-3,1-benzoxazin-4-ones and carbazoles from the same starting materials palladium catalyst. selectivity is controlled by oxidant. Silver oxide promotes C(sp3)-H activation/C-O cyclization to provide H)-3,1-benzoxazin-4-ones, while copper acetate contributes C(sp2)-H activation/decarboxylative arylation afford...

The use of drugs derived from benzothiadiazine, which is a bicyclic heterocyclic benzene derivative, has become widespread treatment for diseases such as hypertension (treated with diuretics bendroflumethiazide or chlorothiazide), low blood sugar non-diuretic diazoxide), the human immunodeficiency virus, among others. In this work, we have investigated interactions benzothiadiazine basic components cell membranes and solvents, phospholipids, cholesterol, ions, water. analysis mutual...

The synthesis of N-heterocycles quinoxalines has been developed by an efficient protocol one-pot annulation alkynes with o-phenylenediamines. A variety were prepared in good to high yields the presence catalytic amount iodine as a catalyst.

Using Molecular Dynamics simulations, we propose a new lipid-like compound that can target both oncogenic GDP/GTP-bound KRAS4B-G12D mutant and PDE- δ so it foster drug discovery research on the RAS family beyond.

A novel decarboxylative N-arylation of indole-2-carboxylic acids with aryl halides is developed. The reaction proceeds efficiently in the presence Cu2O as catalyst to give corresponding N-aryl indoles high yields. This synthetic method shows good functional group tolerance and offers an alternative route construct indoles.

Abstract The use of drugs derived from benzothiadiazine, a bicyclic heterocyclic benzene derivative, has become widespread treatment for diseases such as hypertension, low blood sugar or the human immunodeficiency virus, among others. In this work we have investigated interactions benzothiadiazine and several selected derivatives designed in silico , with basic components cell membranes solvents phospholipids, cholesterol water. analysis mutual microscopic is central importance to elucidate...

Abstract Cyclic diguanosine monophosphate (c-di-GMP) is a ubiquitous bacterial secondary messenger, with diverse functions, many of which are yet to be uncovered. Stemming from an Escherichia coli proteome microarray, we found that c-di-GMP bound 23S rRNA methyltransferases (RlmI and RlmE). methylation assays showed inhibits RlmI activity, thereby modulating ribosome assembly. Based on molecular dynamic simulation mutagenesis studies, binds at residues R64, R103, G114, K201. Structural...

ABSTRACT The guanine exchange factor SOS1 is a crucial node into the positive feedback regulation of KRAS signaling pathway. Currently, KRAS-SOS1 interactions and downstream effector proteins has become new hotspot in development KRAS-driven cancer therapies. However, detailed dynamic mechanisms SOS1-catalyzed GDP extraction impact mutations remain unknown. Herein, main from oncogenes by means are disclosed described with full details at atomic-level. For GDP-bound wild-type KRAS, four amino...

The NRAS-mutant subset of melanoma is one the most aggressive and lethal types associated with poor overall survival. Unfortunately, a low understanding dynamic behavior has lead to lack clinically approved therapeutic agents able directly target NRAS oncogenes. In this work, accurate local structures its mutants have been fully explored through corresponding free energy surfaces obtained by microsecond scale well-tempered metadynamics simulations. Free calculations are crucial reveal...

The NRAS-mutant subset of melanoma is one the most aggressive and lethal types associated with poor overall survival.

可见光诱导的 2-(苄基氨基)苯甲酰胺合成 4(3H)-喹唑啉酮( a 上海交通大学系统生物医学研究院 系统生物医学教育部重点实验室 上海 200240) ( b 上海交通大学化学化工学院 c 上海交通大学医学院附属同仁医院 200336) d 上海市手性药物分子工程重点实验室 摘要 发展了一种环境友好的可见光诱导的反应.该方法在简单、温和的反应条件下可以通过 2-(苄基氨基)苯甲酰胺 来高效合成 4(3H)-喹唑啉酮化合物.不使用任何金属、光催化剂和其他添加剂, 仅在室温下用 blue LED 照射, 反应就 可以顺利进行并高收率得到相应的喹唑啉酮化合物. 该反应具有反应底物范围广、官能团兼容性好、操作简单等优点, 同时可进行克级反应.

Activated KRAS-G12D mutations are the one of most frequent oncogenic drivers in human cancers. Unfortunately, no therapeutic agent directly targeting has been clinically approved yet, with such mutated species remaining undrugged. Notably, cofactor Mg 2+ is closely related to function small GTPases, but investigation done yet on when associated KRAS. Herein, through microsecond scale molecular dynamics simulations we have found that plays a crucial role conformational changes KRAS-GDP...

Abstract The NRAS-mutant subset of melanoma represents the most aggressive and deadliest types associated with poorer overall survival. Unfortunately, for more than 40 years, no therapeutic agent directly targeting NRAS mutations have been clinically approved yet. Herein, based on microsecond scale molecular dynamics simulations, concept NRAS-Q61 mutation classification was firstly proposed. Q61 positively charged (Q61R Q61K) classified together, a specific targetable pocket, while NRAS-Q61L...

Abstract One of the most common drivers in human cancer is KRAS4B. In recent years, promising KRAS targeted drug development has attracted significant new research interest and reignited field RAS therapeutics. To signal, oncogenic KRAS4B not only requires a sufficient nucleotide exchange, but also needs to recruit effectors by exposing its effector-binding sites while anchoring plasma membrane where KRAS4B-mediated signaling events occur. Phosphodiesterase- δ plays an important role...

ABSTRACT KRAS oncogenes are the largest family of mutated RAS isoforms, participating in about 30% all cancers. Due to their paramount medical importance, enormous effort is being devoted development inhibitors using clinical tests, wet-lab experiments and drug design, this a preliminary step process creating new drugs, prior synthesis testing. One central aspect drugs characterization species that can be used for treatment. In aim we propose computational framework based on combined...