In silico screening of indinavir-based compounds targeting proteolytic activity in HIV PR: binding pocket fit approach
- 407 Downloads
The intense research on small molecule inhibitors of Human immunodeficiency virus (HIV)-protease (PR) has produced a diverse class of chemical scaffolds which includes clinically available HIV PR inhibitors (PRI). Till now, these inhibitors are insignificant for targeting proteolytic activity and few drug molecules on alterations can enhance the inhibition of PR enzyme. Here, we developed a method for screening of new hits from Cambridge structural database, based on binding mode of indinavir interaction participating atoms. Knowledge-based ligand screening technique approximately informs that new hits are also having same binding mode-like indinavir interaction patterns. Considering the importance of ligand fitting in binding pocket, we developed induced-fit models for each compound and we obtained accurate energy values in terms of binding and interaction energy. We found that newly search molecules are interacting better than known drug—indinavir and these new compounds are comparatively having better drug-like property. Finally, we demonstrated that pocket specific docking, energy utilization, interactions, and ADME for screened compounds are showing new hit compounds of indinavir are better HIV PRI and these new compounds can also show better activity in in vivo and in vitro conditions.
KeywordsBinding energy HIV CSD Indinavir Interaction energy Induced-fit docking Protease
Cambridge structural database
Optimized potential for liquid simulation
Authors of the study, Chandrabose Selvaraj and Sunil Kumar Tripathi thanking the Alagappa University (AURF) and Department of Science and Technology (DST), New Delhi, for the research fellowship and facility provided for this study. The authors thank an anonymous referee for the valuable suggestion.
- Adachi M, Ohhara T, Kurihara K, Tamada T, Honjo E, Okazaki N, Arai S, Shoyama Y, Kimura K, Matsumura H, Sugiyama S, Adachi H, Takano K, Mori Y, Hidaka K, Kimura T, Hayashi Y, Kiso Y, Kuroki R (2009) Structure of HIV-1 protease in complex with potent inhibitor KNI-272 determined by high-resolution X-ray and neutron crystallography. Proc Natl Acad Sci USA 106:4641–4646PubMedCrossRefGoogle Scholar
- Battle GM, Ferrence GM, Allen FH (2010) Applications of the Cambridge structural database in chemical education. J Appl Crystallogr 43:1208–1223Google Scholar
- Bruno IJ, Cole JC, Edgington PR, Kessler M, Macrae CF, McCabe P, Pearson J, Taylor R (2002) New software for searching the Cambridge structural database and visualizing crystal structures. Acta Crystallogr B 58:389–397Google Scholar
- Jiang JK, Ghoreschi K, Deflorian F, Chen Z, Perreira M, Pesu M, Smith J, Nguyen DT, Liu EH, Leister W, Costanzi S, O’Shea JJ, Thomas CJ (2008) Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550). J Med Chem 51:8012–8018Google Scholar
- Miller JF, Brieger M, Furfine ES, Hazen RJ, Kaldor I, Reynolds D, Sherrill RG, Spaltenstein A (2005) Novel P1 chain-extended HIV protease inhibitors possessing potent anti-HIV activity and remarkable inverse antiviral resistance profiles. Bioorg Med Chem Lett 15:3496–3500PubMedCrossRefGoogle Scholar
- Reddy KK, Singh SK, Dessalew N, Tripathi SK, Selvaraj C (2011) Pharmacophore modelling and atom-based 3D-QSAR studies on N-methyl pyrimidones as HIV-1 integrase inhibitors. J Enzyme Inhib Med Chem. doi: 10.3109/14756366.2011.590803
- Sengupta D, Verma D, Naik PK (2007) Docking mode of delvardine and its analogues into the p66 domain of HIV-1 reverse transcriptase: screening using molecular mechanics-generalized born/surface area and absorption, distribution, metabolism and excretion properties. J Biosci 32:1307–1316PubMedCrossRefGoogle Scholar