Albany 2015:Book of Abstracts

Albany 2015
Conversation 19
June 9-13 2015
©Adenine Press (2012)

Combination of e-pharmacophore modeling, multiple docking strategies and molecular dynamic simulations to discover of novel antagonists of BACE1

Beta-site amyloid precursor protein cleaving enzyme (BACE1 or β-secretase), an aspartic protease responsible for ramping up of Aβ -40/42 peptide fragments by cleaving APP that conciliate for the production of senile plaques and neurofibrillary tangles. Thus it leads to the non-specific road blocks for physical transport and neuro transmitters elevating the hippocampal neuronal damage which eases the memory deficits in Alzheimer's disease (AD). Imparted fundamental role of β-secretase in the formation of Aβ peptide leading to AD, it has been a major therapeutic target for AD intervention, hence was targeted in the present work. One hundred and twenty nine crystal structures were refined with respective co-crystal ligands to generate 129 e-pharmacophore models based on the interaction energy (Ravichand et al., 2013) and from which five common e-pharmacophores (fig. 1) were derived. Based on the common e-pharmacophores, a ligand dataset of 2250 compounds were deduced from the shape based and geometry based similarity screening against more than one million compounds from nine established in-house library of small molecules using PHASE v4.1.Multiple docking strategies such as rigid receptor docking (RRD), QPLD and IFD were performed (Du et al., 2011). Three stage RRD (HTVS, SP, XP) was carried out using Glide v6.5 resulted 23 leads.The resulted 23 leads were compared to 129 co-crystal ligands, 7 best leads were obtained which were further taken for QPLD, IFD and MM-GBSA analysis. Lead1 had the least docking score, lower binding free energy and better binding orientation towards BACE1 (fig. 2). To analyze the stability of the BACE1-lead1 dock complex was subjected to 10 ns MD simulations in Desmond v3.8 and found to be stable (fig. 3).The results from multiple docking analysis and MD simulations affirmed that lead1 might be a promising inhibitor for efficient inhibition of BACE1 activity in reduced Aβ production for treating AD.


I highly acknowledge ICMR, New Delhi, for sanctioning ICMR-SRF (BIC/11(04)/2014). Authors are highly thankful to DBT, Ministry of Science and Technology, Govt. of India for supporting research at SVIMS Bioinformatics center (BT/BI/04/055/2001, 22nd Sep 2006).

    Du, J, Sun, H, Xi, L, Li, J, Yang, Y, Liu, H&Yao, X. (2011). Molecular modeling study of checkpoint kinase 1 inhibitors by multiple docking strategies and prime/MM-GBSA calculation. J ComputChem32, 2800-2809.

    Ravichand, P, Dharmarajan, S, Perumal, Y, Ramakrishna, V. (2013) Multiple e-Pharmacophore Modeling Combined with High-Throughput Virtual Screening and Docking to Identify Potential Inhibitors of β-Secretase (BACE1). Mol. Inf.32, 385-398.

Natarajan Pradeep*
Manne Munikumar
Sandeep Swargam
Kanipakam Hema
Katari Sudheer Kumar
Amineni Umamaheswari**

Bioinformatics Centre
Department of Bioinformatics
Sri Venkateswara Institute of Medical Science University
Andhra Pradesh 517507, India
*Presenting Author
**Corresponding Author

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