Drug molecule design method and device for inherent disordered protein

Abstract

The invention discloses a drug molecule design method and device for inherent disordered protein. The method comprises the following steps: constructing a protein initial three-dimensional structure according to an amino acid sequence of inherent disordered protein, performing enhanced dynamic simulation sampling on the protein initial three-dimensional structure until convergence to obtain a conformation ensemble of the protein, and performing thermodynamic property analysis to obtain a thermodynamic important state; selecting a central conformation after intensified dynamics simulation trajectory clustering, then carrying out classical molecular dynamics simulation on the central conformation, constructing a Markov state model according to a simulation trajectory, carrying out iterative molecular dynamics simulation until the Markov state model meets a standard, and then analyzing the Markov state model, obtaining kinetic properties and kinetic important states therefrom; and performing deep docking treatment and molecular generation treatment according to the thermodynamic important state and the dynamic important state, so as to obtain candidate active drug molecules capable of acting on the inherent disordered protein.

Description

technical field [0001] The present invention relates to the field of molecular design, in particular to a drug molecular design method, device, computer equipment and computer storage medium for inherently disordered proteins. Background technique [0002] Intrinsically disordered proteins (IDPs) are a newly discovered class of proteins that cannot be folded into a clear and unique three-dimensional structure under natural conditions, but have biological functions. Intrinsically disordered proteins cannot be described by a fixed conformation, but must be represented by an ensemble of structures composed of many different conformations. At present, there are many experiments that can detect the structural properties of intrinsically disordered proteins, but due to the constraints of experimental conditions and the disordered nature of intrinsically disordered proteins, there are certain limitations in the experimental observation of intrinsically disordered proteins. [0003...

AI Technical Summary

Problems solved by technology

These traditional enhanced sampling methods have certain disadvantages: the excessively high temperature selected by the copy exchange method will produce unnatural protein conformations; the reaction coordinates selected by the multivariate dynamics method are limited, and it is often difficult to accurately describe complex protein systems

In addition, more importantly, the previous drug molecular design methods for inherently disordered proteins were limited to simple molecular dynamics simulations, which could not accurately describe their thermodynamic properties; There are some rate-limiting states or central states, which are not well studied and have many limitations in the design of drug molecules

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