Multistep Reaction Based De Novo Drug Design: Generating Synthetically Feasible Design Ideas.

We describe a "multistep reaction driven" evolutionary algorithm approach to de novo molecular design. Structures generated by the approach include a proposed synthesis path intended to aid the chemist in assessing the synthetic feasibility of the ideas that are generated. The methodology is independent of how the design ideas are scored, allowing multicriteria drug design to address multiple issues including activity at one or more pharmacological targets, selectivity, physical and ADME properties, and off target liabilities; the methods are compatible with common computer-aided drug discovery "scoring" methodologies such as 2D- and 3D-ligand similarity, docking, desirability functions based on physiochemical properties, and/or predictions from 2D/3D QSAR or machine learning models and combinations thereof to be used to guide design.

Comparison of Composer and ORCHESTRAR.

Although the number of known protein structures is increasing, the number of protein sequences without determined structures is still much larger. Three-dimensional (3D) protein structure information helps in the understanding of functional mechanisms, but solving structures by X-ray crystallography or NMR is often a lengthy and difficult process. A relatively fast way of determining a protein's 3D structure is to construct a computer model using homologous sequence and structure information.

OptiDock: virtual HTS of combinatorial libraries by efficient sampling of binding modes in product space.

Products from combinatorial libraries generally share a common core structure that can be exploited to improve the efficiency of virtual high-throughput screening (vHTS). In general, it is more efficient to find a method that scales with the total number of reagents (Sigma growth) rather with the number of products (Pi growth). The OptiDock methodology described herein entails selecting a diverse but representative subset of compounds that span the structural space encompassed by the full library.

Practical aspects of lyophilization using non-aqueous co-solvent systems.

Non-aqueous co-solvent systems have been evaluated for their potential use in the freeze-drying of pharmaceutical products. The advantages of using these non-aqueous solvent systems include: increased drug wetting or solubility, increased sublimation rates, increased pre-dried bulk solution or dried product stability, decreased reconstitution time, and enhancement of sterility assurance of the pre-dried bulk solution. Conversely, the potential disadvantages and issues which must be evaluated include: the proper safe handling and storage of flammable and/or explosive solvents, the special facilities or equipment which may be required, the control of residual solvent levels, the toxicity of the remaining solvent, qualification of an appropriate GMP purity, the overall cost benefit to use of the solvent, and the potential increased regulatory scrutiny.