RATIONAL SMALL MOLECULE DESIGN

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1 RATIONAL SMALL MOLECULE DESIGN NBD is involved in the application of computational chemistry tools aimed at accelerating, streamlining and optimizing the design of small molecules in early discovery. In order to perform most of rational small molecule design NBD is endowed, among a series of different softwares, with one of the most highly regarded platforms in the industry, the Schrodinger suite of programs. This platform allows developing standard cheminformatics and small molecule rational design tasks efficiently and reliably. However, NBD is additionally deeply engaged in the development of unique, innovative computational chemistry technologies which allow the company to complement the industry standard. These core technologies are designed to tackle a series of current limitations in the field of cheminformatics, ligand-based and structure-based small molecule design.

2 1.1 CHEMINFORMATICS NBD scientists have the experience and tools needed to handle cheminformatics problems such as small molecule library management, chemical space and diversity analysis, in silico combinatorial library construction, drug-likeness and in silico safety profiling.. Scientific compound management, drug-likeness prediction, molecular diversity calculations and property-based database filtering. Store, manage and query 2D databases, explore and predict drug-likeness, compare libraries in terms of chemical space coverage, and filter any subset based on physico-chemical and predicted biological properties. Combinatorial library creation, target-focused libraries. Build and enumerate virtual combinatorial libraries based on predetermined or proprietary building blocks, construct core-based libraries around a particular scaffold or combine building blocks based on any series of chemical reactions. Safety profiling. Predict biological properties and toxicology effects from the 2D structure, analyze in vitro data related to biological activity and toxicology prediction. Development of tailored solutions. NBD can develop any cheminformatics tailored solution in a timely and efficient manner.

3 PROPRIETARY TECHNOLOGY ChemistriX. Generic virtual compound library of IP-liability free, original fragment-like and lead-like molecules. One of the core technologies being currently developed at NBD is an innovative database of fragment-like and lead-like compounds specifically designed to complement the chemical space available in compound catalogues. This library, ChemistriX has been built and will steadily grow following three premises: (i) the chemical reactions leading to them must be thoroughly known and validated by an expert panel of medicinal chemists; (ii) the chemical cores must be underrepresented in currently available screening compound libraries; and (iii) the chemical cores must be attractive from an IP-perspective. The library is currently composed of ca. 1 million compounds and ready for virtual screening.

4 1.2 LIGAND-BASED SMALL MOLECULE DESIGN NBD scientists have all tools needed to implement a ligand-based approach to the design of new small molecules with biological activity, from 2D similarity to 3D molecular alignment and shape and pharmacophore-based perception and screening. 2D similarity searching and screening, 2D QSAR. Screen libraries against a query molecule in terms of 2D similarity with a variety of approaches and fingerprints, cluster compounds and classify them based on scaffold. Ligand-based molecular alignment, pharmacophore perception scaffold hopping. Align molecules based on their 3D structure, determine the most important pharmacophoric features responsible for biological activity and exploit them for scaffold hopping. Hit finding via pharmacophore-based virtual screening. Once a pharmacophore is defined, search 3D compound databases and catalogues to find novel hits represented by alternative scaffolds with similar 3D arrangement of chemical features. Shape-based hit finding. If the bioactive conformation of an active molecule is known, search 3D compound databases and catalogues to find novel hits represented by alternative scaffolds with similar shape.

5 1.3 STRUCTURE-BASED SMALL MOLECULE DESIGN NBD have ample experience in structure-based methods applied in drug discovery projects both from an academic and an industrial perspective. NBD is endowed with all tools needed to implement a structure-based approach to the design of new small molecules with biological activity, from target druggability and flexibility assessment, to docking, in silico fragment screening, molecular dynamics and homology modeling. docking, in silico fragment screening, molecular dynamics and homology modeling. Binding site identification, druggability measurement and detection of possible allosteric sites. Detect sites and cavities capable of binding a small organic molecule and determine their level of druggability with a series of tools that handle the macromolecule either as a rigid or flexible particle. Flexibility assessment based on multiple technologies such as MD, MC, NM. Assess the overall flexibility and the conformational landscape of any binding site of a target with a variety of simulation techniques such as Molecular Dynamics, Monte- Carlo and Normal Modes. Docking-based binding mode determination. Determine the binding mode of a small molecule or a peptide to the macromolecular receptor with classical docking techniques either on a single structure or an ensemble of structures generated by either experiment or simulation. Docking-based virtual screening. Enrich any library for actives against a target by way of high throughput docking and rapidly screen compound catalogues in search of hits. Covalent docking Determine the binding mode of a covalent inhibitor to the macromolecular receptor with covalent docking. Hit-to-lead optimization calculations guided by simulation to improve potency, selectivity and physico-chemical properties. Accurately parametrize promising hits and simulate them in the active site of the receptor in order to gain insight on where to expand them, study the solvation at the ligand-receptor interface and align the structures with other members of the receptor family to guide and optimize selectivity In silico assisted drug reprofiling. Find new potential activities for known drugs by way of structural similarity, docking and simulation. Homology model building of proteins and receptors. Generate homology models of receptors based on closest templates with available 3D structure and optimize their binding sites by way of simulation.

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