Computational Drug Design

Free Energy (FE) calculations based in statistical mechanics are the most accurate and rigorous way to estimate the absolute and relative binding affinities during ‘Lead optimization’ and ‘Scaffold Hopping’ in Drug Discovery as well as computing the thermodynamic stability of alternate drug crystal polymorphs during Drug Development.

The relative free energy can be calculated by performing an ‘alchemical transformation’ between two related ligands (A and B) or tautomers or between two crystal polymorphs via the Einstein crystal state. These are typically done employing thermodynamic integration (TI, estimating reversible work), free energy perturbation (FEP, exponential method, estimating relative probability), Multi-state Bennett Acceptance Ratio (MBAR) or a non-equilibrium method.

These methods require performing Molecular Dynamics (MD) simulations at a number of non-physical intermediate states that connect the end-states (A and B) to obtain a converged FE estimate and thus are computationally expensive.

‘MaldE Scientific’ have developed a proprietary Green Alchemical Free Energy Calculation Algorithm combining soft-core potentials with thermodynamic integration and perturbation to obtain an accurate relative free energy estimate from MD simulation of a single-state as opposed to the standard methods, which require 15–20 intermediate states, resulting in >90% reduction in the carbon footprint of computation.

Additional Validation (Coming soon …)

For Consultative and Collaborative Partnership, please contact malde@maldescientific.com