Free Energy Calculations in Drug Discovery Seminar Course by Dr. Avraham Samson Tomer Meirson MD-PhD student

Introduction – Free Energy of Gibbs 2

3 Introduction – Free Binding Energy Potential Energy A + B A --- B AB

Overview – Measuring Affinity Experimentally 4 SPR – Surface Plasmon Resonance ITC – Isothermal Titration Calorimetry FP – Fluorescence Polarization

Overview – Measuring Affinity Computationally 5 Molecular Docking No dynamics No solvent ∆G calculation Dynamic Implicit solvent ∆G calculation Dynamic Explicit solvent ∆∆G calculation FEP – Free Energy of Perturbation MM/GBSA – Molecular Mechanics General Born Surface Area

Why FEP? Current computational methods are good for posing but bad for assessing the affinity 6

Objectives – FEP Development 7 Accurate estimation of binding affinity Alternative to biochemical assays Massive synthesis Can be avoided Enhanced Drug Discovery

Methods - FEP 8

Combinatorial Chemistry 9 In combinatory chemistry an unlimited number of molecular constructions can be made FEP uses “alchemical” technique in which one molecule transforms gradually into another in order to calculate the relative binding energy accurately

Alchemistry 10

Method – Alchemistry and the Abstract Lambda 11

Results – FEP representatives 12

Results 13

Results 14

Protein FEP for Mutation Resistance 15

FEP Requirements and Limitations 16

FEP Requirements and Limitations 17

Conclusions 18

Acknowledgment 19

Questions ? 20