Poor biopharmaceutical performance of Biopharmaceutical Classification System (BCS) class II drug molecules is a major hurdle in the design and development of pharmaceutical formulations. Anisotropic surface chemistry of different facets in crystalline material affects physicochemical properties, such as wettability, of drugs. In the present investigation, a molecule-centered approach is presented toward crystal habit modification of celecoxib (CEL) and its effect on oral bioavailability. Two crystal habits of CEL, acicular crystal habit (CEL-A) and a plate-shaped crystal habit (CEL-P), were obtained by recrystallization from toluene at 25 and 60 °C, respectively. Compared to CEL-A, CEL-P exhibited significantly faster dissolution kinetics in aqueous media and significantly higher C max and shorter T max in an oral bioavailability study. The significant enhancement in dissolution and biopharmaceutical performance of CEL-P was attributed to its more abundant hydrophilic surfaces compared to CEL-A. This conclusion was supported by wettability and surface free energy determination from contact angle measurements and surface chemistry determination by X-ray photoelectron spectroscopy (XPS), crystal structure modeling, and crystal face indexation.

Cell motility is essential for protozoan and metazoan organisms and typically relies on the dynamic turnover of actin filaments. In metazoans, monomeric actin polymerises into usually long and stable filaments, while some protozoans form only short and highly dynamic actin filaments. These different dynamics are partly due to the different sets of actin regulatory proteins and partly due to the sequence of actin itself. Here we probe the interactions of actin subunits within divergent actin filaments using a comparative dynamic molecular model and explore their functions using Plasmodium, the protozoan causing malaria, and mouse melanoma derived B16-F1 cells as model systems. Parasite actin tagged to a fluorescent protein (FP) did not incorporate into mammalian actin filaments, and rabbit actin-FP did not incorporate into parasite actin filaments. However, exchanging the most divergent region of actin subdomain 3 allowed such reciprocal incorporation. The exchange of a single amino acid residue in subdomain 2 (N41H) of Plasmodium actin markedly improved incorporation into mammalian filaments. In the parasite, modification of most subunit–subunit interaction sites was lethal, whereas changes in actin subdomains 1 and 4 reduced efficient parasite motility and hence mosquito organ penetration. The strong penetration defects could be rescued by overexpression of the actin filament regulator coronin. Through these comparative approaches we identified an essential and common contributor, subdomain 3, which drives the differential dynamic behaviour of two highly divergent eukaryotic actins in motile cells.

The recently developed AlphaFold2 (AF2) algorithm predicts proteins’ 3D structures from amino acid sequences. The open AlphaFold protein structure database covers the complete human proteome. Using an industry-leading molecular docking method (Glide), we investigated the virtual screening performance of 37 common drug targets, each with an AF2 structure and known holo and apo structures from the DUD-E data set. In a subset of 27 targets where the AF2 structures are suitable for refinement, the AF2 structures show comparable early enrichment of known active compounds (avg. EF 1%: 13.0) to apo structures (avg. EF 1%: 11.4) while falling behind early enrichment of the holo structures (avg. EF 1%: 24.2). With an induced-fit protocol (IFD-MD), we can refine the AF2 structures using an aligned known binding ligand as the template to improve the performance in structure-based virtual screening (avg. EF 1%: 18.9). Glide-generated docking poses of known binding ligands can also be used as templates for IFD-MD, achieving similar improvements (avg. EF 1% 18.0). Thus, with proper preparation and refinement, AF2 structures show considerable promise for in silico hit identification.