A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the development of high quality drug candidates. Structure-based drug design (SBDD) methods are becoming increasingly powerful, versatile and more widely used. This review summarizes current developments in structure-based virtual screening and receptor-based pharmacophores, highlighting achievements as well as challenges, along with the value of structure-based lead optimization, with emphasis on recent examples of successful applications for the identification of novel active compounds.Keywords: Structure-based drug design, medicinal chemistry, virtual screening, QSAR, pharmacophores. STRUCTURE-BASED DRUG DESIGNThe performance of biochemical processes and cell mechanisms are dependent upon complex and multiple noncovalent intermolecular interactions between proteins and small-molecule modulators. The understanding of the structural and chemical binding properties of important drug targets in biologically relevant pathways allows the design of small molecules capable of regulating or modulating specific target functions in the body that are closely linked to human diseases and disorders, through multiple intermolecular interactions within a well-defined binding pocket [1][2][3][4]. In general, the identification of promising hits for further optimization is a major challenge faced by the both pharmaceutical and academic laboratories. Although the trial-anderror nature is inherent in drug research, rational concepts and modern computational methods have become widely employed for lead selection and optimization.The use of three-dimensional (3D) protein structure information in the development of new biologically active molecules, which is termed Structure-Based Drug Design (SBDD), is a well-established, successful and highly attarctive strategy used by academic and pharmaceutical research laboratories worldwide [3][4][5][6][7][8]. As a creative and knowledgedriven approach, an essential requirement for structure-based studies is a substantial understanding of the spatial and energetic aspects that affect the binding affinities of proteinligand complexes. Considering that the shape and chemical nature of the binding site of a specific target protein are known, and the possible intermolecular interactions between ligands and the protein within its active site have been identified, this qualified information can be directly employed for the identification of new ligands and the optimization of lead compounds. This opens new possibilities to boost the search for lead molecules and to limit the number of compounds that need to be evaluated experimentally.Hits can be identified through the docking of smallmolecule ligands (selected from databases of chemical structures) into protein active sites or by using receptorbased pharmacophore models. Furthermore, drug candidates can be designed de novo by improving the complementary binding properties of lead compounds and the r...

Drug design is a process driven by innovation and technological breakthroughs involving a combination of advanced experimental and computational methods. A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the optimization of leads into drug candidates. Quantitative structure-activity relationship (QSAR) methods are among the most important strategies that can be applied for the successful design of small molecule modulators having clinical utility. Hologram QSAR (HQSAR) is a modern 2D fragment-based QSAR method that employs specialized molecular fingerprints. HQSAR can be applied to large data sets of compounds, as well as traditional-size sets, being a versatile tool in drug design. The HQSAR approach has evolved from a classical use in the generation of standard QSAR models for data correlation and prediction into advanced drug design tools for virtual screening and pharmacokinetic property prediction. This paper provides a brief perspective on the evolution and current status of HQSAR, highlighting present challenges and new opportunities in drug design.

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Based on classical colchicine site ligands and a computational model of the colchicine binding site on beta tubulin, two classes of chalcone derivatives were designed, synthesized and evaluated for inhibition of tubulin assembly and toxicity in human cancer cell lines. Docking studies suggested that the chalcone scaffold could fit the colchicine site on tubulin in an orientation similar to that of the natural product. In particular, a 3,4,5-trimethoxyphenyl ring adjacent to the carbonyl group appeared to benefit the ligand-tubulin interaction, occupying the same subcavity as the corresponding moiety in colchicine. Consistent with modeling predictions, several 3,4,5-trimethoxychalcones showed improved cytotoxicity to murine acute lymphoblastic leukemia cells compared with a previously described parent compound, and inhibited tubulin assembly in vitro as potently as colchicine. The most potent chalcones inhibited the growth of human leukemia cell lines at nanomolar concentrations, caused microtubule destabilization and mitotic arrest in human cervical cancer cells, and inhibited human breast cancer cell migration in scratch wound and Boyden chamber assays.