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This paper uses newly developed and extended quantum chemical methods in an attempt to advance the knowledge of the relationship between the variation of several local atomic descriptors of the electronic structure and the variation of the inhibitory capacity of a group of reversible and irreversible inhibitors of hepatitis C virus NS5B polymerase. Good structure-activity relationships were obtained for both kinds of compounds. Some processes are charge-, orbital- and/or steric-controlled. The action mechanisms seem to be different for reversible and irreversible inhibitors. Also, good QSAR equations were obtained for the activities of these compounds in a cellular replicon assay and for pharmacokinetic profiles. The local atomic hardness seems to give a good account of the interaction of the drugs with apolar sites of the partner (enzyme, receptor, etc.). This is the first time that a purely quantum-chemical index is able to deal directly with this kind of interaction. 1 . HCV belongs to the genus Hepacivirus and is a member of the family Flaviviridae. HCV is a positive-sense single-stranded RNA virus with a single open frame of about 9600 nucleosides 2-23 . The viral genome encodes a polyprotein of more than 3000 amino acids. The polyprotein is divided into structural and nonstructural precursor regions. The structural protein contains the nucleocapsid core protein and two glycoproteins, E1 and E2. The nonstructural proteins located downstream are NS2, NS3, NS4A, NS4B, NS5A and NS5B. Because of their essential role in the replication of HCV, intensive research has been focused on finding drugs directly targeting these nonstructural proteins. NS5B has the key function of replicating HCV's RNA by using the viral positive RNA strand as its template, and catalyzes the polymerization of ribonucleoside triphosphates during RNA replication. NS5B has been and remains a major target for the development of HCV-specific drugs 24-38 (we have included only references from year 2012). It is of interest then to collect more information, coming from other fields of research, about the physical mechanism(s) underlying NS5B inhibition. We have focused our attention on two recent studies on the inhibition of HCV NS5B polymerase by several indole-based compounds. The first one deals with irreversible inhibitors and the second one with reversible ones 39, 40 . This paper uses quantum chemical methods in an attempt to advance the knowledge of the relationship between the variation of several descriptors of the electronic structure and the variation of biological activities for the two abovementioned sets. N j Sm . These indices are very helpful to compare the reactivity of similar atomic positions through a series of molecules because they include the eigenvalue spectrum which is habitually different in each molecular system. The total atomic electrophilic superdelocalizability is associated with the electron-donor capacity and the total atomic nucleophilic superdelocalizability with the electron-acceptor capacity of a given atom. The last bracket of the right side of Eq. 6 contains new local atomic reactivity indices obtained from the analysis of higher terms of the series expansion for i e

journal of the chilean chemical society

QUANTUM CHEMICAL STUDY OF THE RELATIONSHIPS BETWEEN ELECTRONIC STRUCTURE AND PHARMACOKINETIC PROFILE, INHIBITORY STRENGTH TOWARD HEPATITIS C VIRUS NS5B POLYMERASE AND HCV REPLICONS OF INDOLE-BASED COMPOUNDS