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Role of computer-aided drug design in modern drug discovery
Stephani Joy Y. Macalino,홍선혜,GOSUVIJAYAKUMAR,최선 대한약학회 2015 Archives of Pharmacal Research Vol.38 No.9
Drug discovery utilizes chemical biology andcomputational drug design approaches for the efficientidentification and optimization of lead compounds. Chemical biology is mostly involved in the elucidation ofthe biological function of a target and the mechanism ofaction of a chemical modulator. On the other hand, computer-aided drug design makes use of the structuralknowledge of either the target (structure-based) or knownligands with bioactivity (ligand-based) to facilitate thedetermination of promising candidate drugs. Various virtualscreening techniques are now being used by bothpharmaceutical companies and academic research groupsto reduce the cost and time required for the discovery of apotent drug. Despite the rapid advances in these methods,continuous improvements are critical for future drug discoverytools. Advantages presented by structure-based andligand-based drug design suggest that their complementaryuse, as well as their integration with experimental routines,has a powerful impact on rational drug design. In thisarticle, we give an overview of the current computationaldrug design and their application in integrated rational drugdevelopment to aid in the progress of drug discoveryresearch.
Park, Soo-Bong,Bae, Da-Woon,Clavio, Nina Abigail B.,Zhao, Lei,Jeong, Chang-Sook,Choi, Bo Mee,Macalino, Stephani Joy Y.,Cha, Hee-Jeong,Park, Jin-Byung,Lee, Jun Hyuck,Nam, Sang-Jip,Choi, Sun,Kim, Min-Ky American Chemical Society 2018 Journal of agricultural and food chemistry Vol.66 No.40
<P>Curcumin is a yellow-colored ingredient in dietary spice turmeric (<I>Curcuma longa</I> Linn). This nontoxic polyphenol has antitumor, anti-inflammatory, apoptotic, and antioxidant activities. The ingested curcumin is reduced to multihydrated forms with more potent therapeutic potentials by the curcumin reductase (CurA) from commensal <I>Escherichia coli</I>. In this study, we demonstrated that <I>Vibrio vulnificus</I> CurA (<I>Vv</I>CurA) with 87% sequence similarity to the <I>E. coli</I> CurA exhibits the curcumin-reducing activity through spectrophotometric detection of NADPH oxidation and high performance liquid chromatographic analysis of curcumin consumption and product generation. Afterward, we determined the crystal structures of <I>Vv</I>CurA and the <I>Vv</I>CurA/NADPH complex, and made the in silico model of the <I>Vv</I>CurA/NADPH/curcumin ternary complex through induced fit docking. Based on structural information, active site residues that play critical roles in catalysis have been identified and characterized by mutational and kinetic studies, leading us to propose the reaction mechanism of CurA.</P> [FIG OMISSION]</BR>
Hoang, Van-Hai,Ngo, Van T. H.,Cui, Minghua,Manh, Nguyen Van,Tran, Phuong-Thao,Ann, Jihyae,Ha, Hee-Jin,Kim, Hee,Choi, Kwanghyun,Kim, Young-Ho,Chang, Hyerim,Macalino, Stephani Joy Y.,Lee, Jiyoun,Choi, S American Chemical Society 2019 Journal of medicinal chemistry Vol.62 No.17
<P>Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disease whose pathogenesis cannot be defined by one single element but consists of various factors; thus, there is a call for alternative approaches to tackle the multifaceted aspects of AD. Among the potential alternative targets, we aim to focus on glutaminyl cyclase (QC), which reduces the toxic pyroform of β-amyloid in the brains of AD patients. On the basis of a putative active conformation of the prototype inhibitor <B>1</B>, a series of N-substituted thiourea, urea, and α-substituted amide derivatives were developed. The structure-activity relationship analyses indicated that conformationally restrained inhibitors demonstrated much improved QC inhibition in vitro compared to nonrestricted analogues, and several selected compounds demonstrated desirable therapeutic activity in an AD mouse model. The conformational analysis of a representative inhibitor indicated that the inhibitor appeared to maintain the Z-E conformation at the active site, as it is critical for its potent activity.</P> [FIG OMISSION]</BR>