CASE STUDY

Discovery of a novel, potent
ACC inhibitor driven bycomputationally-guided design
and assessment of waterenergetics in the binding site
Collaborative team of scientists from Nimbus Therapeutics
and Schrödinger discover ND-630 for NASH and other liver diseases

Leveraged virtual screening
guided by hydration energetics
to improve potency

Rapidly optimized ADME
properties using structureguided methods“The discovery of ND-630
was one of the first
demonstrations of thepower of rigorous physicsbased computationalmodeling to guide design andsynthesis of a high-qualitydevelopment candidate.”— Robert Abel
Chief Computational Officer
Schrödinger

Resulted in the discovery ofa development candidatein 16 months

Target

ACC1 and ACC2Program
TypeCollaborative program,small moleculePartner

Nimbus Therapeutics

Indication

Type 2 diabetes, fatty liverdisease, non-alcoholicsteatohepatitis

StagePhase 2b clinical trial

DESIGN CHALLENGE
As a key component of the fatty acidsynthesis pathway (FaSyn), inhibitionof acetyl-coenzyme A carboxylase(ACC) is a well validated strategy for theamelioration of metabolic disorders,such as type 2 diabetes, non-alcoholicsteatohepatitis (NASH), and atherosclerotic
vascular disease. ACC consists of twoisoforms — ACC1 and ACC2, locatedin the cytoplasm and mitochondria,respectively. Additionally, ACC comprises
two domains, the biotin carboxylase (BC)and carboxyltransferase (CT) domains, thatcarry out separate enzymatic functions.
Previous efforts have focused on inhibitionof the CT domain, resulting in moleculeswith poor drug-like properties as well as
selectivity issues. In comparison, targeting
the BC domain represented an opportunity
to develop a molecule with both improvedproperties and selectivity. Working
together, scientific teams from Nimbus
Therapeutics and Schrödinger leveraged acomputationally-guided, structure-based
approach to design novel drug candidates.
The goal of this program was to identify
potent and selective inhibitors of the BC
domain of ACC1 and ACC2.

Identifying potent, selective inhibitors
using a virtual screening workflow
guided by hydration energetics
The team initiated the program with a two-pronged virtual screening
workflow against the dimerization site of the BC domain. An available
X-ray structure containing a bound ligand, Soraphen A, was used toguide both structure- and ligand-based screens for molecules thatinterfered with ligand binding and, consequently, enzymatic activity.
Prior to conducting the screens, identification of high-energy hydrationsites within the binding region was performed using WaterMap, astate-of-the-art, structure-based method for assessment of waterenergetics.1 Multiple high-energy hydration sites were identified byWaterMap; intriguingly, these sites were located in a deep, narrow
pocket proximal to Val587 and Tyr683, and close to Soraphen A.
Using these hydration sites and other interactions as constraints,
the team screened a commercially available library via docking withGlide, as well as pharmacophore screening with Phase (followedby docking). From this workflow, 250 chemically diverse molecules
predicted to displace the high-energy hydration sites were evaluatedin vitro. Ultimately, this strategy led to the identification of ND-022,
a low micromolar dual inhibitor of ACC1 and ACC2 and the firstmolecule reported to mimic Soraphen A and inhibit enzyme activity
via interaction within the ACC2 dimerization site (Figure 1).2

Figure 1: Identification of ND-022, a dual inhibitor of ACC1 and ACC2, by locating high-energy, displaceable waters using WaterMap.
(Left) Soraphen A does not displace high-energy waters (red spheres). (Middle) ND-022 displaces high-energy waters and captures
additional potency. (Right) Cocrystal structure of ND-022 complexed with hACC2 BC overlaid with the structure of Soraphen A
complexed with hACC2 BC.2

2

Rapid, structure-guided optimization of ADME
properties results in clinical stage ACC inhibitorOnce a micromolar inhibitor was identified, the teamfocused their efforts on improving ACC2 inhibition,functional potency, and optimizing pharmacokinetics(PK). To achieve improved PK properties and potency,
the team applied two complementary approaches –namely molecular mechanics and quantum mechanics.
Guided by these simulations, four modifications
were hypothesized to impact PK properties favorablywhile maintaining or improving potency. In only 16months, this work culminated in the discovery of ND630 (aka GS-0976, firsocostat), a potential first-in-class,potent, and selective inhibitor of the BC domain ofACC with favorable drug-like properties (Figure 2).2,3
In 2016, the program was acquired by Gilead Sciences.4
In 2017, Gilead presented positive data showing that a20 mg orally administered dose of GS-0976/firsocostat,taken once daily for 12 weeks, led to statisticallysignificant reductions in hepatic steatosis and theliver fibrosis marker TIMP-1, when compared to theplacebo.5 Since then Gilead has prioritized developmentof GS-0976/firsocostat in combination with Novo
Nordisk’s semaglutide, a GLP-1 receptor agonist.

In 2020, a five-arm trial evaluated combinations of Novo
Nordisk’s semaglutide with Gilead’s investigational
FXR agonist cilofexor and/or Gilead’s investigational
ACC inhibitor firsocostat. The trial spanned 24 weeks
and involved 108 patients with NASH. It successfully
met its primary endpoint demonstrating that allregimens were well tolerated in patients with NASH
and mild to moderate fibrosis, with the most common
adverse events as gastrointestinal in nature.6
Furthermore, exploratory efficacy endpoints assessing
biomarkers of liver health at 24 weeks in post-hoc analyses
revealed statistically significant improvements in hepatic
steatosis and liver injury in the combination arms versus
semaglutide alone.6 Encouraged by these results, Gilead andNovo Nordisk are currently evaluating patients in a phase2b trial for the combination.7 Although the clinical trial isongoing, this case study highlights how drugs developedwith Schrödinger technology have strong potential toimpact the lives of patients with high unmet needs.

Figure 2: (Left) Chemical structure of ND-630. (Middle) Cocrystal structure of ND-630 complexed with hACC2 BC. (Right) The nature ofthe amino acid residues interacting with ND-630 in the hACC2 BC dimerization site.23

Enabling digital technologies to drive discovery programs
WaterMap

GlidePhase

Structure-based method forassessing the energetics of water
solvating ligand binding sites forligand optimization

Highly versatile, industry-leading
ligand-receptor docking solution

Pharmacophore modeling solution
for ligand- and structure-based design

Software and services to meet your organization’s needs
Industry-Leading Software Platform
Deploy digital drug discovery workflows using a comprehensive and user-friendly platform for molecularmodeling, design, and collaboration.

Research Enablement Services
Leverage Schrödinger’s team of expert computational scientists to advance your projects through key stages
in the drug discovery process.

Scientific and Technical Support
Access expert support, educational materials, and training resources designed for both novice andexperienced users.

References
1.

Calculating water thermodynamics in the binding site of proteins – Applications of WaterMap to drug discovery.
Cappel et al. Curr. Top. Med. Chem. 2017,17(23), 2586-2598.

2.

Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates
dyslipidemia in rats. Harriman et al. Proc. Natl. Acad. Sci. U S A. 2016 Mar 29, 113(13), E1796-805.

3.

Accelerating drug discovery through tight integration of expert molecular design and predictive scoring. Abel et al.
Curr Opin Struct Biol. 2017, 43, 38-44.

4.

Gilead Sciences announces acquisition of Nimbus Therapeutics’ acetyl-CoA carboxylase (ACC) program for NASH andother liver diseases. Gilead. 2016.

5.

Gilead announces Phase 2 results for GS-0976 in nonalcoholic steatohepatitis (NASH). Gilead. 2017.

6.

Gilead and Novo Nordisk present new data from proof-of-concept trial in NASH. Gilead. 2020.

7.

Gilead and Novo Nordisk expand NASH clinical collaboration. Gilead. 2021.

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