Inhibition mechanism of MRTX1133 on KRASG12D: a molecular dynamics simulation and Markov state model study.

The mutant KRAS was considered as an "undruggable" target for decades, especially KRASG12D. It is a great challenge to develop the inhibitors for KRASG12D which lacks the thiol group for covalently binding ligands. The discovery of MRTX1133 solved the dilemma. Interestingly, MRTX1133 can bind to both the inactive and active states of KRASG12D. The binding mechanism of MRTX1133 with KRASG12D, especially how MRTX1133 could bind the active state KRASG12D without triggering the active function of KRASG12D, has not been fully understood. Here, we used a combination of all-atom molecular dynamics simulations and Markov state model (MSM) to understand the inhibition mechanism of MRTX1133 and its analogs. The stationary probabilities derived from MSM show that MRTX1133 and its analogs can stabilize the inactive or active states of KRASG12D into different conformations. More remarkably, by scrutinizing the conformational differences, MRTX1133 and its analogs were hydrogen bonded to Gly60 to stabilize the switch II region and left switch I region in a dynamically inactive conformation, thus achieving an inhibitory effect. Our simulation and analysis provide detailed inhibition mechanism of KRASG12D induced by MRTX1133 and its analogs. This study will provide guidance for future design of novel small molecule inhibitors of KRASG12D.

[Studies on the extraction of ingredients from Chinese traditional medicine with CO2 supercritical fluid].

OBJECTIVE: To study the extraction technology with CO2 supercritical fluid in Chinese Traditional Medicine by extracting the anthraquinones ingredients from Salvia miltiorrhiza and Polygonum caspidatum. METHOD: Extractions were made under different pressure, temperature, extraction time, entrainer, and the extracts were analyzied by TLC and HPLC. RESULT: The technology could be used in extraction and isolation. Under certain conditions, different contents of the extracts could be obtained. CONCLUSION: CO2 supercritical fluid is good at extracing low polarity ingredients, and it shows the evident individurity in extraction of Chinese herb. The technological factors in industrial usage must be thought of all over.