Platform

Creating exceptional medicines with structure and ReSOLVE™

ReSOLVE™: Integrating the latest advances in machine learning, structural biology, and computational chemistry to model the full spectrum of protein dynamics and design first-in-class and best-in-class small molecule drugs.

Proteins have many biological functions and are in constant motion – rapidly changing their molecular conformations to carry out specific tasks within biological pathways inside a cell. On a molecular level, water is an essential participant in the stability, structure, motion, and function of proteins. Both proteins and molecules that aim to drug them exist in water.

Platform

ReSOLVE™ is the only platform that can: model all conformations of a protein, identify druggable pockets, understand the precise and dynamic water networks of a pocket, and use those water networks to generate a blueprint for small molecule therapeutics, which we refer to as a hydrocophore®.

As a hit identification tool, ReSOLVE™ uniquely uses the hydrocophore® to guide a virtual screen and efficiently identify potential hits. After hits are validated in the wet-lab, they drive additional screening and optimization of chemical matter, as demonstrated by our cGAS program. With ReSOLVE™, we are able to identify novel molecules for targets that have been inaccessible by small molecules to date, and quickly optimize these molecules towards a development candidate.

The HYDROCOPHORE®:
a “blueprint” for small molecule design

Proteins are nanomachines with many conformations. Each conformation changes the contours of known pockets or presents new pockets. Water fills these pockets and potent small molecule drugs effectively displace water from that binding pocket. With ReSOLVE™, we can extract the dynamic water structure of the binding pockets (the hydrocophore®) and use it as a blueprint for the identification and optimization of small molecules. ReSOLVE™ allows us to understand the shape, polarity, and potential druggability of binding pockets at a new level of resolution.

The hydrocophore® enables rapid virtual screening of libraries of billions of compounds to identify potent and structurally unique chemical matter, typically with a higher probability of success than traditional methods. By restricting the virtual screening search to only pursue chemical matter that resembles the blueprint, we generate far fewer virtual hits than traditional methods and only have to wet-lab test a limited number of compounds, thus reducing the cost and time involved in testing potential hits, optimizing only promising chemical matter, and improving our overall efficiency.

Efficient virtual screens that generate NOVEL CHEMICAL MATTER

A new level of resolution with ReSOLVE™

Protein science expertise:
Highly enabled structure-based
drug design

High quality protein target structural information is required to fully take advantage of our unique unrestrained molecular dynamics and solvation analysis tools.

Ventus has deep in-house expertise in protein engineering, expression, and structure determination. This has allowed us to solve high-resolution structures of challenging targets, such as NLRP3 and cGAS, and proceed to structure-based drug design.

Unrestrained molecular dynamics: Modeling and clustering a moving protein’s many conformations

Computer simulations of proteins in motion produce millions of conformations for evaluation. Many existing conformation clustering methods result in configurations that don’t exist in nature and will lead to a dead-end in the drug discovery process.

ReSOLVE™ addresses this limitation by enabling the unbiased modeling of a broad set of configurations for a dynamic protein, including those that are rare.

Accurate modeling of the
dynamic solvation structure of
binding pockets

Traditional methods to identify small molecules that can bind to pockets on proteins are not designed to account for the importance of the dynamic nature of the solvation structure within a binding pocket.

ReSOLVE™ addresses this limitation by modeling the dynamic solvation structure of each conformation to identify a hydrocophore®, a three-dimensional blueprint of an existing pocket.

Partnering opportunities

We are continuously searching for new ReSOLVE™ targets and are interested in discussing collaboration opportunities with potential partners. If you are interested in learning more about ReSOLVE™, please contact us by filling out the form here.

Related publications by Ventus Therapeutics employees

Probing the Dynamic Structure−Function and Structure-Free Energy Relationships of the Coronavirus Main Protease with Biodynamics Theory.

Wan, H. Aravamuthan, V, Pearlstein R. ACS Pharmacol. Transl. Sci. 2020 Nov 6, 3, 6, 1111–1143.

Structure-Based and Property-Driven Optimization of N‐Aryl Imidazoles toward Potent and Selective Oral RORγt Inhibitors.

Hoegenauer K, Kallen J, Jimenez-Nunez E, Strang R, Ertl P, Cooke NG, Hintermann S, Voegtle M, Betschart C, McKay DJJ, Wagner J, Ottl J, Beerli C, Billich A, Dawson J, Kaupmann K, Streiff M, Gobeau N, Harlfinger S, Stringer R, Guntermann C. J. Med. Chem. 2019 Dec 12, 62(23): 10816−10832.

Building New Bridges between in Vitro and in Vivo in Early Drug Discovery: Where Molecular Modeling Meets Systems Biology.

Pearlstein RA, McKay DJJ, Hornak V, Dickson C, Golosov A, Harrison T, Velez-Vega C, Duca J. Current Topics in Medicinal Chemistry 2017, 17, 1-21.

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