R43GM148095

Quantum chemistry methods for rational drug design - project summary

A scalable computational quantum mechanics method for non-covalent protein-ligand interactions will be developed based on "extended" symmetry-adapted perturbation theory (XSAPT), a cubic-scaling, fragment-based approach that is specifically designed for large supramolecular complexes, and which affords a demonstrated accuracy of ;$ 1 KCAL/MO! with respect to the best-available ab initio benchmarks.

In Phase I of this work, we will enhance the efficiency of XSAPT via better parallelization that will enable routine application to protein-ligand models containing 300+ atoms, using only modest computational resources. A bootstrap procedure will be developed to assess the accuracy of the method and a data set will be generated that includes protein-ligand interaction energies and their components: electrostatics, steric repulsion, dispersion, polarization, and charge transfer.

The data set will build upon standard ones derived from crystal structures but will also include nonequilibrium structures as well as small ligand fragments for which crystal structures and other experimental data are not available; the latter are representative of fragment-based drug discovery strategies. These are challenging cases for interaction energy computations that can only be addressed quantitatively by using the predictive power of quantum mechanics, not by empirical scoring functions or by fits to experimental data.

In Phase II, this data set will be used to train a machine learning (ML) model that is capable of ranking-ordering ligand binding energies in a reliable and quantitative way, something that existing scoring functions (even those based on ML) cannot do. Additional Phase II work will integrate the ML-XSAPT scoring function into virtual drug-discovery workflows (including flexible docking protocols), which will facilitate both lead generation and lead optimization in drug discovery, based on quantitative ab initio energetics.

Q-Chem

THE NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES (NIGMS) SUPPORTS BASIC RESEARCH THAT INCREASES OUR UNDERSTANDING OF BIOLOGICAL PROCESSES AND LAYS THE FOUNDATION FOR ADVANCES IN DISEASE DIAGNOSIS, TREATMENT, AND PREVENTION. NIGMS ALSO SUPPORTS RESEARCH IN SPECIFIC CLINICAL AREAS THAT AFFECT MULTIPLE ORGAN SYSTEMS: ANESTHESIOLOGY AND PERI-OPERATIVE PAIN, CLINICAL PHARMACOLOGY ?COMMON TO MULTIPLE DRUGS AND TREATMENTS, AND INJURY, CRITICAL ILLNESS, SEPSIS, AND WOUND HEALING.? NIGMS-FUNDED SCIENTISTS INVESTIGATE HOW LIVING SYSTEMS WORK AT A RANGE OF LEVELSFROM MOLECULES AND CELLS TO TISSUES AND ORGANSIN RESEARCH ORGANISMS, HUMANS, AND POPULATIONS. ADDITIONALLY, TO ENSURE THE VITALITY AND CONTINUED PRODUCTIVITY OF THE RESEARCH ENTERPRISE, NIGMS PROVIDES LEADERSHIP IN SUPPORTING THE TRAINING OF THE NEXT GENERATION OF SCIENTISTS, ENHANCING THE DIVERSITY OF THE SCIENTIFIC WORKFORCE, AND DEVELOPING RESEARCH CAPACITY THROUGHOUT THE COUNTRY.

93.859 - Biomedical Research and Research Training

National Institute of General Medical Sciences (NIGMS) [HHS - NIH]

California United States

State-Wide

PHS 2022-2 Omnibus Solicitation of the NIH, CDC and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed) (PA-22-176)

Amendment Since initial award the End Date has been extended from 11/14/23 to 11/14/24.