The discovery and design of new drugs requires extensive experimental assays that are usually very expensive and time-consuming. To cut down the cost and time of the drug development process and help design effective drugs more efficiently, various computational methods have been developed that are referred to collectively as in silico drug design. These in silico methods can be used to not only determine compounds that can bind to a target receptor but to determine whether compounds show ideal drug-like properties. I have provided solutions to these problems by developing novel methods for molecular simulation and molecular property prediction. Firstly, we have developed a new enhanced sampling MD algorithm called Resampling of Ensembles by Variation Optimization or "REVO" that can generate binding and unbinding pathways of ligand-target interactions. These pathways are useful for calculating transition rates and Residence Times (RT) of protein-ligand complexes. This can be particularly useful for drug design as studies for some systems show that the drug efficacy correlates more with RT than the binding affinity. This method is generally useful for generating long-timescale transitions in complex systems, including alternate ligand binding poses and protein conformational changes. Secondly, we have developed a technique we refer to as "ClassicalGSG" to predict the partition coefficient (log P) of small molecules. log P is one of the main factors in determining the drug likeness of a compound, as it helps determine bioavailability, solubility, and membrane permeability. This method has been very successful compared to other methods in literature. Finally, we have developed a method called "Flexible Topology'' that we hope can eventually be used to screen a database of potential ligands while considering ligand-induced conformational changes. After discovering molecules with drug-like properties in the drug design pipeline, Virtual Screening (VS) methods are employed to perform an extensive search on drug databases with hundreds of millions of compounds to find candidates that bind tightly to a molecular target. However, in order for this to be computationally tractable, typically, only static snapshots of the target are used, which cannot respond to the presence of the drug compound. To efficiently capture drug-target interactions during screening, we have developed a machine-learning algorithm that employs Molecular Dynamics (MD) simulations with a protein of interest and a set of atoms called "Ghost Particles". During the simulation, the Flexible Topology method induces forces that constantly modify the ghost particles and optimizes them toward drug-like molecules that are compatible with the molecular target.
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