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Identification of Pak1 inhibitors using water thermodynamic analysis

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journal contribution
posted on 17.02.2019, 16:15 by Jayashree Biswal, Prajisha Jayaprakash, Rayala Suresh Kumar, Ganesh Venkatraman, Saritha Poopandi, Raghu Rangasamy, Jeyakanthan Jeyaraman

p21-activated kinases (Paks) play an integral component in various cellular diverse processes. The full activation of Pak is dependent upon several serine residues present in the N-terminal region, a threonine present at the activation loop, and finally the phosphorylation of these residues ensure the complete activation of Pak1. The present study deals with the identification of novel potent candidates of Pak1 using computational methods as anti-cancer compounds. A diverse energy based pharmacophore (e-pharmacophore) was developed using four co-crystal inhibitors of Pak1 having pharmacophore features of 5 (DRDRR), 6 (DRHADR), and 7 (RRARDRP and DRRDADH) hypotheses. These models were used for rigorous screening against e-molecule database. The obtained hits were filtered using ADME/T and molecular docking to identify the high affinity binders. These hits were subjected to hierarchical clustering using dendritic fingerprint inorder to identify structurally diverse molecules. The diverse hits were scored against generated water maps to obtain WM/MM ΔG binding energy. Furthermore, molecular dynamics simulation and density functional theory calculations were performed on the final hits to understand the stability of the complexes. Five structurally diverse novel Pak1 inhibitors (4835785, 32198676, 32407813, 76038049, and 32945545) were obtained from virtual screening, water thermodynamics and WM/MM ΔG binding energy. All hits revealed similar mode of binding pattern with the hinge region residues replacing the unstable water molecules in the binding site. The obtained novel hits could be used as a platform to design potent drugs that could be experimentally tested against cancer patients having increased Pak1 expression.


JJ thank the DST- Fund for Improvement of S&T Infrastructure in Higher Educational Institutions (FIST) (SR/FST/LSI-667/2016) (C), DST-Promotion of University Research and Scientific Excellence (PURSE) (No. SR/PURSE Phase 2/38 (G), 2017, Indian Council for Medical Research (ICMR) (No.BIC/12(07)/2015), UGC Research Award (No. F. 30-32/2016(SA-II) dt 18.04.2016), DST-Science and Engineering Research Board (SERB) (No. EMR/2016/000498), Board of Research in Nuclear Sciences (BRNS) (35/14/02/2018-BRNS/35009) and MHRD-RUSA 2.0, New Delhi (F.24-51/2014-U, Policy (TNMulti-Gen), Dept. of Edn. Govt. of India, Dt.09.10.2018). JB is grateful to the UGC OBC National Fellowship (F./2015-16/NFO-2015-17-OBC-PON-29027). A special word of gratitude to Dr. Ravikumar Muttineni, Senior Applications Scientist, Schrodinger and Mr. Vinod, Applications Scientist, Schrodinger for their timely help, views and suggestions to carry out this work.