• Current bioactivity databases are increasing in size, with the question being how to exploit them
• Applications to Mode-of-Action analysis using in silico target prediction will be presented
• A prospective application is ligand design taking bioactivity information against multiple receptors into account, for which experimental validation will be presented

•    What should a toolbox of simple statistical techniques look like for a molecular modeler?
•    Address the issue of method validation given the data typically available
•    Describe some of the advances other fields have made using modern statistical methods

• Application to Ab humanization
• Application to Ab stabilization
• Application to affinity maturation
• Application to novel formats

• CADD encompasses all aspects of drug discovery
• Structurally-informed design and computational power allow applications that were not possible before
• New research directions will be exemplified: bridging in vitro and in vivo

• Structure-based design of HIV protease inhibitors has led to broadly active compounds. The resistance profile is often difficult to understand and better predictive structural modeling is needed
• Proteochemometric modeling is a computational technology that simultaneously uses activity data of multiple compounds on multiple targets. This technology was applied to two large datasets of non-nucleoside HIV reverse transcriptase inhibitors and resulted in improved predictions.
• Water molecules are important in the binding of small molecules to protein targets. WaterMap calculations were used to analyze the SAR of Hepatitis C
NS5a inhibitors, and provided new insights into the activity of these compounds

Most forcefields are based on discrete atom types and discrete bond orders. Consequently, many atom types and explicit parameters are required to cover small molecule chemistry space
Here we present an alternative approach to forcefield parameterization based upon deriving conventional molecular mechanics parameters from 2D Extended Hueckel Theory calculations
This approach has the important advantages of requiring orders of magnitude fewer parameters and a better treatment of electron withdrawal and resonance effects
The parameterization methodology is described along with some initial validation experiments

• Theoretical approaches for the representation of the solvent effect on
structure and reactivity
• Discussion into the different methods available for analysis
• Challenges in computational approaches and how to overcome them

• Recent efforts in the computational evaluation of the thermodynamic properties of water molecules resulted in the development of new promising in silico methods to evaluate the water role in ligand binding.
• GRID (Molecular Discovery), SZMAP (OpenEye), WaterMap (Schrödinger) & 3D-RISM (Chemical Computing Group) used to evaluate the role of the solvent in protein function and druggability, structure-activity relationship elucidation, ligand free energy of binding prediction and ligand residence time evaluation
• Test case applying the methods to the Adenosine A2A receptor, and an extension exploiting a recursive partitioning method (Random Forest)

• Application of structure-based drug design in the identification and optimization of a platform of oral & inhaled p38 inhibitors currently undergoing clinical development for the treatment of COPD
• Use of co-crystal structures to guide different design strategies for oral & inhaled delivery
• Optimising slow onset/offset binding kinetics to enhance duration of drug action
• Current clinical development - results & status

• Structure-based evolution of original fragment hits resulting in identification of novel potent inhibitor
• A summary of tactics and results from the initial fragment-based virtual screening
• Structure-based hypotheses to improve potency and FXi selectivity

• Computational methods for Hit optimization
• Statistical and structure based approaches to determine molecular properties
• Molecules design using SAR
• Case study – Anti-infective Hit to Lead optimization
• Case study – Cardiovascular System Hit identification

• Biophysical methods in drug discovery and their use to faciliate decisions
• Why do we work with Kinetics data?
• How can kinetic data influence in drug discovery projects
• Use of thermodynamic binding signatures in hit optimization. Current status of use and next steps to come

• A public-private partnership under the Innovative Medicines Initiative (IMI) involving large Pharma, academics and SMEs
• An open infrastructure based on semantic technologies for the integration of pharmacological data in the life sciences
• Development of the platform driven by a prioritised set of “real life” drug discovery questions
• Addressing some key challenges: sustainability, provenance, licensing, private data

• The influence of dissociation rate on drug efficacy and duration of action
• Modelling restricted diffusion in micro-anatomic structures and introducing the concept of drug rebinding and its influence on duration of action
• Enhancing the likelihood of rebinding by optimising affinity for the local target environment
• How these phenomena may complicate interpretation of the pharmacology of new drugs

• Rational design of PPI disruptors
• Results of biological profiling
• PPI disruptors with favourable physicochemical properties
• New approaches of identifying druggable PPIs

• The development of small molecule ligands that selectively act on one of the five mAChR subtypes (M1–M5) has proven extremely challenging, primarily owing to the high degree of sequence similarity in the transmembrane core of these receptors
• We characterized the pathway by which drugs bind to and dissociate from the M2 and M3 receptors using long timescale molecular dynamics simulations
• These simulations suggest a metastable drug-binding site in the extracellular vestibule of both receptors, and also provide a potential rationale for the slower dissociation rates of certain M3 antagonists
• Our findings may facilitate the design of improved subtype-selective therapeutics targeting these critical receptors

• The availability of isolated receptor conformations in active and inactive states opens the door to the concept of ‘reverse pharmacology’, whereby the functional pharmacology of ligands can be characterised in a system independent manner by their affinity for a pair (or set) of GPCR conformations
• Rationalisation of the pharmacology observed by ligand docking into the known crystal structures of the A2A receptor: e.g., inverse agonists vs neutral antagonists
• The promise of predicting cellular and in vivo pharmacology of GPCR ligands using this ‘reverse pharmacology’ approach on the basis of affinity constants or even free energy of binding calculations

• Fragment screening options on GPCRs: biophysical vs biochemical screening
• Virtual fragment screening by high throughput docking
    o X-ray structures vs homology models
    o Single conformation vs ensemble docking
• Prospective virtual screening case studies
• Comparative experimental and virtual fragment screening on GPCRs