# Integration of Evolution to Avoid Resistance in Structure Based Drug Design

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $590,475

## Abstract

Integration of Evolution to Avoid Resistance in Structure Based Drug Design
Many of the most deadly diseases that plague our society evolve quickly, challenging our
therapeutic strategies. Drug resistance occurs as a result of this evolution when drug pressure
changes the balance of molecular recognition events, selectively weakening inhibitor binding
while maintaining the biological function of the therapeutic target. Disrupting the therapeutic
target’s activity is necessary but not sufficient to avoid resistance. We hypothesize that the
multi-dimensional landscape of resistance evolution can be elucidated through integration of
experimental and computational data to reveal the key pathways and coupled molecular
mechanisms to resistance. Furthermore, we hypothesize that this strategy can be incorporated
into structure-based drug design to evaluate novel inhibitors.
 Resistance occurs under gradual and persistent drug pressure, and interestingly the
mutations are not limited to the active site of a drug target, but can occur throughout the enzyme
to confer high levels of resistance. The molecular mechanism by which this resistance occurs is
not clear. Our aim is to exploit the rich and versatile experimental data, integrating inhibitor
potency and crystallographic structures with ensemble dynamics in an internally consistent
manner using machine learning to elucidate both the molecular mechanisms of drug resistance
and generate predictive models of inhibitor potency.

## Key facts

- **NIH application ID:** 10437865
- **Project number:** 5R01GM135919-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Celia A. Schiffer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $590,475
- **Award type:** 5
- **Project period:** 2020-09-10 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437865

## Citation

> US National Institutes of Health, RePORTER application 10437865, Integration of Evolution to Avoid Resistance in Structure Based Drug Design (5R01GM135919-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10437865. Licensed CC0.

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