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An infrastructure to mine molecular descriptors for ligand selection on virtual screening.

ABSTRACT: The receptor-ligand interaction evaluation is one important step in rational drug design. The databases that provide the structures of the ligands are growing on a daily basis. This makes it impossible to test all the ligands for a target receptor. Hence, a ligand selection before testing the ligands is needed. One possible approach is to evaluate a set of molecular descriptors. With the aim of describing the characteristics of promising compounds for a specific receptor we introduce a data warehouse-based infrastructure to mine molecular descriptors for virtual screening (VS). We performed experiments that consider as target the receptor HIV-1 protease and different compounds for this protein. A set of 9 molecular descriptors are taken as the predictive attributes and the free energy of binding is taken as a target attribute. By applying the J48 algorithm over the data we obtain decision tree models that achieved up to 84% of accuracy. The models indicate which molecular descriptors and their respective values are relevant to influence good FEB results. Using their rules we performed ligand selection on ZINC database. Our results show important reduction in ligands selection to be applied in VS experiments; for instance, the best selection model picked only 0.21% of the total amount of drug-like ligands.

SUBMITTER: Seus VR

PROVIDER: S-EPMC4000951 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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An infrastructure to mine molecular descriptors for ligand selection on virtual screening.

Seus Vinicius Rosa VR Perazzo Giovanni Xavier GX Winck Ana T AT Werhli Adriano V AV Machado Karina S KS

BioMed research international 20140409

The receptor-ligand interaction evaluation is one important step in rational drug design. The databases that provide the structures of the ligands are growing on a daily basis. This makes it impossible to test all the ligands for a target receptor. Hence, a ligand selection before testing the ligands is needed. One possible approach is to evaluate a set of molecular descriptors. With the aim of describing the characteristics of promising compounds for a specific receptor we introduce a data ware ...[more]

PMID: 24812613

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Project description:Structure-based virtual screening (SBVS) is a widely used method in silico drug discovery. It necessitates a receptor structure or binding site to predict the binding pose and fitness of a ligand. Therefore, the performance of the SBVS is affected by the protein conformation. The most frequently used method in SBVS is the protein-ligand docking program, which utilizes atomic distance-based scoring functions. Hence, they are highly prone to sensitivity towards variation in receptor structure, and it is reported that the conformational change significantly drops the performance of the docking program. To address the problem, we have introduced a novel program of SBVS, named PL-PatchSurfer. This program makes use of molecular surface patches and the Zernike descriptor. The surfaces of the pocket and ligand are segmented into several patches by the program. These patches are then mapped with physico-chemical properties such as shape and electrostatic potential before being converted into the Zernike descriptor, which is rotationally invariant. A complementarity between the protein and the ligand is assessed by comparing the descriptors and geometric distribution of the patches in the molecules. A benchmarking study showed that PL-PatchSurfer2 was able to screen active molecules regardless of the receptor structure change with fast speed. However, the program could not achieve high performance for the targets that the hydrogen bonding feature is important such as nuclear hormone receptors. In this paper, we present the newer version of PL-PatchSurfer, PL-PatchSurfer3, which incorporates two new features: a change in the definition of hydrogen bond complementarity and consideration of visibility that contains curvature information of a patch. Our evaluation demonstrates that the new program outperforms its predecessor and other SBVS methods while retaining its characteristic tolerance to receptor structure changes. Interested individuals can access the program at kiharalab.org/plps3.

Project description:Various toxicity and pharmacokinetic evaluations as screening experiments are needed at the drug discovery stage. Currently, to reduce the use of animal experiments and developmental expenses, the development of high-performance predictive models based on quantitative structure-activity relationship analysis is desired. From these evaluation targets, we selected 50% lethal dose (LD50), blood-brain barrier penetration (BBBP), and the clearance (CL) pathway for this investigation and constructed predictive models for each target using 636-11,886 compounds. First, we constructed predictive models using the DeepSnap-deep learning (DL) method and images of compounds as features. The calculated area under the curve (AUC) and balanced accuracy (BAC) were, respectively, 0.887 and 0.818 for LD50, 0.893 and 0.824 for BBBP, and 0.883 and 0.763 for the CL pathway. Next, molecular descriptors (MDs) of compounds were calculated using Molecular Operating Environment, alvaDesc, and ADMET Predictor to construct predictive models using the MD-based method. Using these MDs, we constructed predictive models using DataRobot. The calculated AUC and BAC were, respectively, 0.931 and 0.805 for LD50, 0.919 and 0.849 for BBBP, and 0.900 and 0.807 for the CL pathway. In this investigation, we constructed predictive models combining the DeepSnap-DL and MD-based methods. In ensemble models using the mean predictive probability of the DeepSnap-DL and MD-based methods, the calculated AUC and BAC were, respectively, 0.942 and 0.842 for LD50, 0.936 and 0.853 for BBBP, and 0.908 and 0.832 for the CL pathway, with improved predictive performance observed for all variables compared with either single method alone. Moreover, in consensus models that adopted only compounds for which the results of the two methods agreed, the calculated BAC for LD50, BBBP, and the CL pathway were 0.916, 0.918, and 0.847, respectively, indicating higher predictive performance than the ensemble models for all three variables. The predictive models combining the DeepSnap-DL and MD-based methods displayed high predictive performance for LD50, BBBP, and the CL pathway. Therefore, the application of this approach to prediction targets in various drug discovery screenings is expected to accelerate drug discovery.

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An infrastructure to mine molecular descriptors for ligand selection on virtual screening.

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An infrastructure to mine molecular descriptors for ligand selection on virtual screening.

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