AmberMDrun Programmable Framework And Virtual Screening Of ACE2 Protein Inhibitor

Molecular Dynamics(MD)simulation is a widely-used simulation method and has become a powerful tool in areas such as biomolecular simulation and computeraided drug design(CADD).By simulating the interaction between receptor macromolecules(such as proteins and nucleic acids)and other small molecules,their binding behavior and binding free energy can be studied and predicted.However,performing MD simulations requires complex input steps and force field settings,which can be challenging for beginners and require lengthy training.Therefore,we have developed a program called Amber MDrun aimed at simplifying the preparation process and running flow of MD simulations.This program can automatically prepare the input files required for Amber MD simulations,automatically equilibrate the system,run Amber MD and output,and predict the binding free energy of receptor ligands.By using Amber MDrun,users can easily and quickly perform MD simulations,allowing them to focus more on scientific problems themselves.Amber MDrun is an open-source and scalable tool with a high-performance and convenient python interface.The core code is written in C++ for efficient operation.The program provides flexible setting options that can be modified freely to suit users’ needs.All source code and documentation can be obtained from https://github.com/9527567/Amber MDrun.We hope that this tool can provide a more convenient and efficient MD simulation assistance tool for researchers and Amber MD beginners.Using our developed MD simulation framework,we conducted virtual screening studies on ACE2 protein.In this study,we selected the traditional Chinese medicine database TCMIO as the small molecule compound library for virtual screening,which contains more than 126,973 small molecule compounds.In the preliminary smina docking screening,we used the Python multithreading library to screen the TCMIO database for small molecule compounds with initial scoring lower than-12 kcal/mol and selected 665 small molecule compounds with better docking scores.Further using the docking module of MOE software,we conducted a more precise induced fit docking screening on these compounds and screened out small molecule compounds with MOE docking score lower than-13 kcal/mol.Finally,we screened out 17 potentially valuable compounds from the TCMIO database of 126,973 compounds.Next,we performed a 50 ns MD simulation on these 17 small molecule compounds to calculate their binding free energy(MM-PBSA).We selected small molecule compounds with binding free energy lower than-60 kcal/mol,among which four had good binding free energy and were considered potential ACE2 candidate inhibitors.These small molecule compounds include CHEMBL3650543,CHEMBL-3654085,CHEMBL3650631,and CHEMBL2337904.Their binding free energies are-70,-60.1,-58.33,and-54.40 kcal/mol,respectively.In this study,we designed the Amber automatic running simulation program tool Amber MDrun for the first time and verified its reliability through examples.With the help of the Amber MDrun tool,we conducted high-throughput virtual screening of ACE2 inhibitors in the TCMIO database and obtained several compounds with potential,among which CHEMBL3650543 with a binding free energy of-70 kcal/mol can be considered a higher potential ACE2 inhibitor.