1026701-89-2Relevant academic research and scientific papers
Substrate envelope-designed potent HIV-1 protease inhibitors to avoid drug resistance
Nalam, Madhavi N.L.,Ali, Akbar,Reddy, G.S. Kiran Kumar,Cao, Hong,Anjum, Saima G.,Altman, Michael D.,Yilmaz, Nese Kurt,Tidor, Bruce,Rana, Tariq M.,Schiffer, Celia A.
, p. 1116 - 1124 (2013/10/01)
Summary The rapid evolution of HIV under selective drug pressure has led to multidrug resistant (MDR) strains that evade standard therapies. We designed highly potent HIV-1 protease inhibitors (PIs) using the substrate envelope model, which confines inhib
Design, synthesis, and biological and structural evaluations of novel HIV-1 protease inhibitors to combat drug resistance
Parai, Maloy Kumar,Huggins, David J.,Cao, Hong,Nalam, Madhavi N. L.,Ali, Akbar,Schiffer, Celia A.,Tidor, Bruce,Rana, Tariq M.
, p. 6328 - 6341 (2012/09/07)
A series of new HIV-1 protease inhibitors (PIs) were designed using a general strategy that combines computational structure-based design with substrate-envelope constraints. The PIs incorporate various alcohol-derived P2 carbamates with acyclic and cyclic heteroatomic functionalities into the (R)-hydroxyethylamine isostere. Most of the new PIs show potent binding affinities against wild-type HIV-1 protease and three multidrug resistant (MDR) variants. In particular, inhibitors containing the 2,2-dichloroacetamide, pyrrolidinone, imidazolidinone, and oxazolidinone moieties at P2 are the most potent with Ki values in the picomolar range. Several new PIs exhibit nanomolar antiviral potencies against patient-derived wild-type viruses from HIV-1 clades A, B, and C and two MDR variants. Crystal structure analyses of four potent inhibitors revealed that carbonyl groups of the new P2 moieties promote extensive hydrogen bond interactions with the invariant Asp29 residue of the protease. These structure-activity relationship findings can be utilized to design new PIs with enhanced enzyme inhibitory and antiviral potencies.
HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants
Altman, Michael D.,Ali, Akbar,Reddy, G. S. Kiran Kumar,Nalam, Madhavi N. L.,Anjum, Saima Ghafoor,Cao, Hong,Chellappan, Sripriya,Kairys, Visvaldas,Fernandes, Miguel X.,Gilson, Michael K.,Schiffer, Celia A.,Rana, Tariq M.,Tidor, Bruce
, p. 6099 - 6113 (2008/09/21)
The acquisition of drug-resistant mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors predicted to stay within a consensus substrate volume in the binding site. Two rounds of design, synthesis, experimental testing, and structural analysis were carried out, resulting in a total of 51 compounds. Improvements in design methodology led to a roughly 1000-fold affinity enhancement to a wild-type protease for the best binders, from a Ki of 30-50 nM in round one to below 100 pM in round two. Crystal structures of a subset of complexes revealed a binding mode similar to each design that respected the substrate envelope in nearly all cases. All four best binders from round one exhibited broad specificity against a clinically relevant panel of drug-resistant HIV-1 protease variants, losing no more than 6-13-fold affinity relative to wild type. Testing a subset of second-round compounds against the panel of resistant variants revealed three classes of inhibitors: robust binders (maximum affinity loss of 14-16-fold), moderate binders (35-80-fold), and susceptible binders (greater than 100-fold). Although for especially high-affinity inhibitors additional factors may also be important, overall, these results suggest that designing inhibitors using the substrate envelope may be a useful strategy in the development of therapeutics with low susceptibility to resistance.
