Drug discovery can nowadays rely on computational approaches, which can focus on specific drug binding sites and substrate-molecule interactions modes. While the molecular docking paradigm can provide some guidance in identifying and developing novel drugs, a complete mapping of the free energy of drug-substrate interaction is an emerging paradigm towards rational drug design. The free energy landscape paradigm allows for an explicit assessment of factors affecting interaction strength, as well as all entropic contributions, which are essential to understand binding mode competition, as well as conformational degrees of freedom and the role of solvation. To exemplify this paradigm, we have focused on DNA secondary structure G-quadruplexes, which can control oncogene expression, and are therefore important targets in cancer research. The specific binding of gold carbene complexes to G4 was investigated by metadynamics, to asses drug-substrate bonding specificity and variety of binding poses. Metadynamics explores chemical processes along selected reaction coordinates, so-called collective variables (CV), efficiently achieving comprehensive scans of the totality of binding modes over the whole DNA G4 system. This makes for an overall unbiased mechanistic exploration of the system of interest, one that not only allows for a detailed investigation of binding mechanisms, but also includes the relative free energy ranking of all possible binding modes (poses).  Computationally, the strategy can be focused on identifying suitable CVs, which can drive the exploration of local conformational changes and global binding modes. This provides a simulation platform, which can be used to screen novel drugs, by testing their competition directly on the substrate, in order to identify the best candidate. Furthermore, the approach can be developed to include elements of DNA secondary structure formation, for a complete reconnaissance of drug selectivity and dynamics. <br/>

Drug discovery by molecular dynamics: Role of the free energy landscape

2019 Fall National Meeting

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