Simulations Plus Completes Molecule Design Phase of Second NCE Project, Issues RFQs for Molecule Synthesis

Keywords: COX-2 inhibition, molecule design, NCE (new chemical entity) project
Division: PBPK

Simulations Plus, Inc. (NASDAQ:SLP), a leading provider of simulation and modeling software and consulting services for pharmaceutical discovery and development, today announced that it has completed the molecule design phase of its second NCE (new chemical entity) project, and is issuing requests for quotes to synthesize the new compounds for testing. This second NCE project follows the Company’s successful project that was completed last year to design new molecules to inhibit the malaria parasite.

Dr. Robert Clark, director of life sciences for Simulations Plus, said: “Our target for this second NCE project is cyclooxygenase-2 (COX-2). We selected this particular target because:

  • The withdrawals of rofecoxib (marketed as Vioxx, Ceoxx, and Ceeoxx) and valdecoxib (marketed as Bextra) left only celecoxib (marketed as Celebrex, the first approved COX-2 inhibitor) on the market.
  • The drugs were withdrawn because of potential cardiac toxicity, possibly caused by high inhibition of COX-2 coupled with low inhibition of COX-1. We believe that designing new molecules that can bind to both COX-2 and COX-1, with greater binding to COX-1 than the withdrawn drugs, may be the key to achieving safe COX-2 inhibition.
  • Sufficient data existed in the public domain to enable us to build models to predict the ability of new molecules to bind to both COX-2 and COX-1.”

Dr. Clark continued: “Generating good lead molecules to progress to preclinical work has often required synthesizing and testing hundreds or thousands of compounds over several years. Combining our ADMET Design Suite™ (MedChem Studio™, MedChem Designer™, and ADMET Predictor™), along with our GastroPlus™ software, we design and evaluate thousands of new molecules to select a set of promising lead candidates quickly and economically. The COX-2 inhibitor design project involved:

  • Finding public domain data for molecules that had measured activities for both COX-2 and COX-1.
  • Using our MedChem Studio software to analyze the public domain molecular structures by clustering molecules into classes with similar common substructures (scaffolds).
  • Building predictive models for COX-2 and COX-1 affinity using the ADMET Modeler™ module within ADMET Predictor.
  • Analyzing the public domain molecules within various classes with respect to their ability to bind to both COX-2 and COX-1, as well as their predicted properties for solubility, permeability, metabolism, and various potential toxicities.
  • Generating new molecular structures using the de novo molecule design capabilities in MedChem Studio.
  • Screening the thousands of new molecules with ADMET Predictor to eliminate those with unacceptable ADMET Risk™.
  • Finalizing the molecule designs with MedChem Designer.
  • Selecting the most interesting molecules for analysis with our GastroPlus software to estimate the dosing regimen needed for each of them, considering not only affinity to the target but all relevant ADMET properties that affect oral absorption, metabolism, and plasma concentration-time histories.
  • Preparing requests for quotes for chemical synthesis companies and contract research organizations (CROs) to make a selected set of compounds and to run a small battery of tests to confirm our predictions.”

Walt Woltosz, chairman and CEO of Simulations Plus, added: “We are announcing this project prior to synthesis of the molecules, as we did for the malaria project. When the test results are in, we will announce them, regardless of the outcome. We believe this demonstrates our high confidence in the effectiveness of our software tools. Keep in mind that our goal is not to be a pharmaceutical company, but to demonstrate that our ADMET Design Suite provides unique capabilities to generate high-quality lead molecules for specific targets in a fraction of the time and cost that have normally been required. Lead molecules are not final drug products, but are intended to provide good starting points that can be refined to become real drugs.”