Computer-aided drug design at Boehringer Ingelheim

Abstract

Computer-Aided Drug Design (CADD) is an integral part of the drug discovery endeavor at Boehringer Ingelheim (BI). CADD contributes to the evaluation of new therapeutic concepts, identifies small molecule starting points for drug discovery, and develops strategies for optimizing hit and lead compounds. The CADD scientists at BI benefit from the global use and development of both software platforms and computational services. A number of computational techniques developed in-house have significantly changed the way early drug discovery is carried out at BI. In particular, virtual screening in vast chemical spaces, which can be accessed by combinatorial chemistry, has added a new option for the identification of hits in many projects. Recently, a new framework has been implemented allowing fast, interactive predictions of relevant on and off target endpoints and other optimization parameters. In addition to the introduction of this new framework at BI, CADD has been focusing on the enablement of medicinal chemists to independently perform an increasing amount of molecular modeling and design work. This is made possible through the deployment of MOE as a global modeling platform, allowing computational and medicinal chemists to freely share ideas and modeling results. Furthermore, a central communication layer called the computational chemistry framework provides broad access to predictive models and other computational services.

Accounting for the Central Role of Interfacial Water in Protein–Ligand Binding Free Energy Calculations

“…Note that the RMSE values exclude the results for KEK~KWK, for which all four methods yield errors of over 10 kcal mol -1 ; this perturbation is examined separately in Section 4.3.3. As shown in the following subsection, the difference between Methods [1,2] and Methods [3,4] versus when they are removed prior to initial solvation (Method 3). Indeed, these two methods yield free energies that differ by up to 18 kcal mol -1 (KWK~KKK, Table 2).…”

Insights into Noncovalent Binding Obtained from Molecular Dynamics Simulations

“…Molecular simulation is a powerful tool that provides valuable insight into the relationship between molecular structure and the macroscopic properties of matter. It has reached a level of maturity that allows its use in actual industrial settings for example in the pharmaceutical , or chemical industry . Its important role in life sciences is documented through various examples showing how purely computational work may drive new experimental efforts , .…”

Busca Virtual De Compostos Bioativos: Conceitos E Aplicações

“…Como exemplo do uso destas ferramentas, podemos citar: na identificação de hits 52 e de compostos líderes (do inglês leads); 53 no processo de otimização dos compostos líderes; na predição e otimização de suas propriedades ADMET e no desenvolvimento de formulação, entre outros. [54][55][56][57]…”