Date

Date: Thursday 18th January, 2024
Time: 2pm GMT / 3pm CET / 9am EST / 6:30pm IST
Duration: 45 minutes
Format: Webinar

Abstract 

G protein-coupled receptors (GPCRs) are a very large and important class of drug targets. They are also a very difficult class in terms of modeling with adequate accuracy the necessarily many atoms that constitute the protein, ligands, membrane lipids and solvent. Faster and more accurate computational solutions are required for these challenging systems. In this session we discuss a workflow using computational chemistry methods that are available within Cresset’s CADD software platform, Flare™ to arrive at accurate binding free energies for a set of P2Y1 ligands bound to a lipid-exposed binding site.  

The methods are: 

• Molecular Dynamics (MD)  
• Water analysis solving the Ornstein-Zernike equation (3D-RISM) 
• Alignment of ligands for FEP (Conf Hunt & Align) 
• Relative binding free-energy (RBFE) perturbation theory (Flare FEP). 

We show that using MD, water analysis and careful ligand alignment prior to RBFE calculations can result in reliable predictions for protein-ligand binding affinities even in the case where the ligand is at the lipid-protein interface. Until recently the computational cost of such a large system (93,255 atoms) would be prohibitively large. Implementing methods that ensure a stable and appropriately hydrated binding site (a suitable snapshot of in vivo binding action) as input to the RBFE calculation results in an efficient process for setting up the RBFE job to yield accurate results. The RBFE calculation itself is improved, in terms of efficiency, by the implementation of adaptive Lambda (λ) schedules and automated intermediate generation. The results that will be presented show that the predicted binding free energy of 30 ligands matches the measured experimental affinity closely (mean unsigned error is 1.17 kcal/mol). This difficult computational problem can now be solved relatively quickly with good accuracy by using these methods, and, in principle this workflow could be extended to further membrane protein targets in drug discovery.  

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• Grow your professional network—surround yourself with like-minded professionals and participate in dedicated opportunities to expand your network.
• Learn from your peers and experts in the field—Through a variety of learning formats and topical interest areas, ISPOR 2024 brings you the content necessary to keep up with the rapidly expanding HEOR field.

This must-attend event welcomes all healthcare stakeholders and is directly relevant to researchers and academicians, assessors and regulators, payers and policy makers, the life sciences industry, healthcare providers, and patient engagement organizations. This global scientific event will cover key HEOR topics, including:

• Clinical Outcomes
• Economic Evaluation
• Epidemiology and Public Health
• Health Policy and Regulatory
• Health Service Delivery and Process of Care
• Health Technology Assessment
• Medical Technologies
• Methodological and Statistical Research
• Organizational Practices
• Patient-Centered Research
• Real-World Data and Information Systems
• Real-World Evidence  
• Study Approaches

The post Visit Certara at Booth #312 at ISPOR US 2024 appeared first on MassBio.