Abstract
Rational drug design aims to develop pharmaceutical agents that impart maximal therapeutic benefits via their interaction with their intended biological targets. In the past several decades, advances in computational tools that inform wet-lab techniques have aided the development of a wide variety of new medicines with high efficacies. Nonetheless, drug development remains a time and cost intensive process. In this work, we have developed a computational pipeline for assessing how individual atoms contribute to a ligand’s effect on the structural stability of a biological target. Our approach takes as input a protein-ligand resolved PDB structure file and systematically generates all possible ligand variants. We assess how the atomic-level edits to the ligand alter the drug’s effect via a graph theoretic rigidity analysis approach. We demonstrate, via four case studies of common drugs, the utility of our pipeline and corroborate our analyses with known biophysical properties of the medicines, as reported in the literature.
Highlights
The drug discovery and development process has advanced greatly over the last few decades
The metrics are the average change in rigidity distance (RD) when a single atom is cut from a ligand, and the average rigidity distance (RD) when a pairwise set of atoms is contained in the ligand variant
In the heat maps generated from the PairCut analysis using Protein-Ligand complex Engineering Through Rigidity Analysis (PETRA) (Figure 9), Myristic Acid (MYR) has a larger overall change in RD, meaning the wildtype Human serum albumin (HSA) has more of a change in its rigid cluster when atoms are removed from the ligand
Summary
The drug discovery and development process has advanced greatly over the last few decades This is in part due to both an increased understanding of the biochemistry and biophysics of protein-ligand interactions and to the improvement in wet-lab methods of in vitro screening of novel drugs. Wet-lab methods offer the option to scan through thousands of compounds using techniques, such as high-throughput screening [1] or deep mutational scanning [2] With this increased understanding of protein-ligand interactions, many novel approaches to drug design have been created both in silico and in vitro. Pharmacophore methods, which focus on the chemical activity of the ligand and the interactions between the proteins and ligand, have been helpful in aiding the drug discovery process These methods need to still be improved in efficiency and efficacy in order to be used with high success in the drug design process [16]. Is our approach quick—needing, at most, hours of compute time—compared to wet lab experiments, but it assesses the role of each atom in the engineered drug, which provides a level of detail that is not accessible via most other methods
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