Structure elucidation of small organic molecules by contemporary computational chemistry methods
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Online ISSN 1976-3786 Print ISSN 0253-6269
REVIEW
Structure elucidation of small organic molecules by contemporary computational chemistry methods Chung Sub Kim1 · Joonseok Oh2,3 · Tae Hyun Lee1
Received: 31 August 2020 / Accepted: 21 October 2020 © The Pharmaceutical Society of Korea 2020
Abstract Small molecules derived from natural sources such as plants, fungi, bacteria, or synthetic materials have served as promising drug candidates for a long time. Unambiguous determination of chemical structures of these natural/synthetic molecules is a prerequisite for their development into new drugs. Despite the significant development of modern analytical tools it is still challenging to accomplish full structural assignment. In the last decades, computational chemistry methods using quantum mechanics and molecular mechanics theories followed by sophisticated statistical approaches have been rapidly developed. Such in silico platforms have widely and successfully been used to characterize and revise the structures of natural/synthetic products. In this review, we summarize contemporary computational approaches coupled with statistical methods for structure elucidation of small organic molecules. Among these approaches available, we opted for several relevant case studies in which the stereochemistry/structures of natural products were elucidated using these combinatorial methods. Keywords Structure elucidation · Computational chemistry · Stereochemistry · Quantum mechanics (QM) · Natural products · Nuclear magnetic resonance (NMR) · Statistical analysis
* Chung Sub Kim [email protected] 1
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
2
Department of Chemistry, Yale University, New Haven, CT 06520, USA
3
Chemical Biology Institute, Yale University, West Haven, CT 06516, USA
Introduction Stereochemistry is a subdiscipline of chemistry that studies spatial arrangement of atoms in molecules. Stereoisomers with different stereochemistry may show different biological activities, thus their stereochemical properties should be considered in the discovery, design, and development of new drugs (Agranat et al. 2002). There are many pharmaceutical cases in which stereochemistry affects drugs’ potency and/ or adverse effect. The thalidomide tragedy is the most wellknown case in the pharmaceutical history (Agranat et al. 2002). Thalidomide was used to treat morning sickness during pregnancy in the 1950s and early 1960s. When the thalidomide was first marketed in 1957 in West Germany, it was used as a racemate, mixture of two enantiomers. However, later it was found that the S-form of thalidomide caused severe birth defects such as embryotoxic and teratogenic effect unlike its R-form (Fig. 1). Since then, thalidomide had been withdrawn from the market for over 30 years until it was approved for treatment of leprosy in 1998. Penicillin and chloramphenicol, which are the most widely used antibiotics, have three and two stereogenic centers, respectively; however, only the (2S,5R,6R)-dia
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