1,179 research outputs found
High Throughput Virtual Screening with Data Level Parallelism in Multi-core Processors
Improving the throughput of molecular docking, a computationally intensive
phase of the virtual screening process, is a highly sought area of research
since it has a significant weight in the drug designing process. With such
improvements, the world might find cures for incurable diseases like HIV
disease and Cancer sooner. Our approach presented in this paper is to utilize a
multi-core environment to introduce Data Level Parallelism (DLP) to the
Autodock Vina software, which is a widely used for molecular docking software.
Autodock Vina already exploits Instruction Level Parallelism (ILP) in
multi-core environments and therefore optimized for such environments. However,
with the results we have obtained, it can be clearly seen that our approach has
enhanced the throughput of the already optimized software by more than six
times. This will dramatically reduce the time consumed for the lead
identification phase in drug designing along with the shift in the processor
technology from multi-core to many-core of the current era. Therefore, we
believe that the contribution of this project will effectively make it possible
to expand the number of small molecules docked against a drug target and
improving the chances to design drugs for incurable diseases.Comment: Information and Automation for Sustainability (ICIAfS), 2012 IEEE 6th
International Conference o
Protein side-chain placement: probabilistic inference and integer programming methods
The prediction of energetically favorable side-chain conformations is a fundamental element in homology modeling of proteins and the design of novel protein sequences. The space of side-chain conformations can be approximated by a discrete space of probabilistically representative side-chain conformations (called rotamers). The problem is, then, to find a rotamer selection for each amino acid that minimizes a potential energy function. This is called the Global Minimum Energy Conformation (GMEC) problem. This problem is an NP-hard optimization problem. The Dead-End Elimination theorem together with the A* algorithm (DEE/A*) has been successfully applied to this problem. However, DEE fails to converge for some complex instances. In this paper, we explore two alternatives to DEE/A* in solving the GMEC problem. We use a probabilistic inference method, the max-product (MP) belief-propagation algorithm, to estimate (often exactly) the GMEC. We also investigate integer programming formulations to obtain the exact solution. There are known ILP formulations that can be directly applied to the GMEC problem. We review these formulations and compare their effectiveness using CPLEX optimizers. We also present preliminary work towards applying the branch-and-price approach to the GMEC problem. The preliminary results suggest that the max-product algorithm is very effective for the GMEC problem. Though the max-product algorithm is an approximate method, its speed and accuracy are comparable to those of DEE/A* in large side-chain placement problems and may be superior in sequence design.Singapore-MIT Alliance (SMA
Rational Design of Small-Molecule Inhibitors of Protein-Protein Interactions: Application to the Oncogenic c-Myc/Max Interaction
Protein-protein interactions (PPIs) constitute an emerging class of targets for pharmaceutical intervention pursued by both industry and academia. Despite their fundamental role in many biological processes and diseases such as cancer, PPIs are still largely underrepresented in today's drug discovery. This dissertation describes novel computational approaches developed to facilitate the discovery/design of small-molecule inhibitors of PPIs, using the oncogenic c-Myc/Max interaction as a case study.First, we critically review current approaches and limitations to the discovery of small-molecule inhibitors of PPIs and we provide examples from the literature.Second, we examine the role of protein flexibility in molecular recognition and binding, and we review recent advances in the application of Elastic Network Models (ENMs) to modeling the global conformational changes of proteins observed upon ligand binding. The agreement between predicted soft modes of motions and structural changes experimentally observed upon ligand binding supports the view that ligand binding is facilitated, if not enabled, by the intrinsic (pre-existing) motions thermally accessible to the protein in the unliganded form.Third, we develop a new method for generating models of the bioactive conformations of molecules in the absence of protein structure, by identifying a set of conformations (from different molecules) that are most mutually similar in terms of both their shape and chemical features. We show how to solve the problem using an Integer Linear Programming formulation of the maximum-edge weight clique problem. In addition, we present the application of the method to known c-Myc/Max inhibitors.Fourth, we propose an innovative methodology for molecular mimicry design. We show how the structure of the c-Myc/Max complex was exploited to designing compounds that mimic the binding interactions that Max makes with the leucine zipper domain of c-Myc.In summary, the approaches described in this dissertation constitute important contributions to the fields of computational biology and computer-aided drug discovery, which combine biophysical insights and computational methods to expedite the discovery of novel inhibitors of PPIs
A comprehensive comparison of metaheuristics for the repetition-free longest common subsequence problem
This paper deals with an NP-hard string problem from the bio-informatics field: the repetition-free longest common subsequence problem. This problem has enjoyed an increasing interest in recent years, which has resulted in the application of several pure as well as hybrid metaheuristics. However, the literature lacks a comprehensive comparison between those approaches. Moreover, it has been shown that general purpose integer linear programming solvers are very efficient for solving many of the problem instances that were used so far in the literature. Therefore, in this work we extend the available benchmark set, adding larger instances to which integer linear programming solvers cannot be applied anymore. Moreover, we provide a comprehensive comparison of the approaches found in the literature. Based on the results we propose a hybrid between two of the best methods which turns out to inherit the complementary strengths of both methods.Peer ReviewedPostprint (author's final draft
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