A successful Crystal Structure Prediction case study on Efavirenz, an anti-HIV drug
Avantium Pharma and Avant-garde Materials Simulation GmbH (AMS) have successfully performed a Crystal Structure Prediction case study on Efavirenz, an anti-HIV drug. In a comprehensive structure prediction program, the most stable forms were accurately reproduced, in addition to several other known forms.
Figure 1: Molecular structure of Efavirenz
The Crystal Structure Prediction study was performed with full flexibility of the Efavirenz molecules. In the first step, a tailor-made forcefield was generated for the compound, after which crystal structure generation was performed for all 230 spacegroups with one and with two molecules in the asymmetric unit cell. The structure generation was >99% complete within the applicable energy window. After the structures were generated and ranked in lattice energy, the most promising structures were re-ranked using advanced quantum mechanical calculations, dispersion-corrected DFT. The CSP study took about 5 weeks of computational time on a 256-core high-performance computer cluster.
On the experimental side, after a small screen at Avantium and review of the patent landscape, eight distinct solid forms were identified. From simulated powder patterns of the structures predicted, easy comparison with the experimental XRPD's quickly gave the good agreement with the computational results: the two most stable forms at room temperature were reproduced as the two most stable forms in the prediction (see Figure 2). Additional forms were also found, even the structure of a known solvate.
Figure 2: Overlay of predicted experimental forms B (right) and C (left). Form C is the stable form at room temperature.