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Journal of Computer-aided Molecular Design

P Chellapandi, R Prathiviraj, A Prisilla
Malaria is a life-threatening mosquito-borne blood disease caused by infection with Plasmodium parasites. Anti-malarial drug resistance is a global threat to control and eliminate malaria and therefore, it is very important to discover and evaluate new drug targets. The 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase (IspD) homolog is a second in vivo target for fosmidomycin within isoprenoid biosynthesis in malarial parasites. In the present study, we have deciphered the sequence-structure-function integrity of IspD homologs based on their evolutionary imprints...
February 19, 2019: Journal of Computer-aided Molecular Design
Eva Nittinger, Paul Gibbons, Charles Eigenbrot, Doug R Davies, Brigitte Maurer, Christine L Yu, James R Kiefer, Andreas Kuglstatter, Jeremy Murray, Daniel F Ortwine, Yong Tang, Vickie Tsui
Targeting the interaction with or displacement of the 'right' water molecule can significantly increase inhibitor potency in structure-guided drug design. Multiple computational approaches exist to predict which waters should be targeted for displacement to achieve the largest gain in potency. However, the relative success of different methods remains underexplored. Here, we present a comparison of the ability of five water prediction programs (3D-RISM, SZMAP, WaterFLAP, WaterRank, and WaterMap) to predict crystallographic water locations, calculate their binding free energies, and to relate differences in these energies to observed changes in potency...
February 12, 2019: Journal of Computer-aided Molecular Design
Nataraj Sekhar Pagadala
To develop potent drugs that inhibit the activity of influenza virus RNA dependent RNA polymerase (RdRp), a set of compounds favipiravir, T-705, T-1105 and T-1106, ribavirin, ribavirin triphosphate viramidine, 2FdGTP (2'-deoxy-2'-fluoroguanosine triphosphate) and AZT-TP (3'-Azido-3'-deoxy-thymidine-5'-triphosphate) were docked with a homology model of IAV RdRp from the A/PR/8/34/H1N1 strain. These compounds bind to four pockets A-D of the IAV RdRp with different mechanism of action. In addition, AZT-TP also binds to the PB1 catalytic site near to the tip of the priming loop with a highest ΔG of - 16...
February 9, 2019: Journal of Computer-aided Molecular Design
Arkadii Lin, Dragos Horvath, Gilles Marcou, Bernd Beck, Alexandre Varnek
The previously reported procedure to generate "universal" Generative Topographic Maps (GTMs) of the drug-like chemical space is in practice a multi-task learning process, in which both operational GTM parameters (example: map grid size) and hyperparameters (key example: the molecular descriptor space to be used) are being chosen by an evolutionary process in order to fit/select "universal" GTM manifolds. After selection (a one-time task aimed at optimizing the compromise in terms of neighborhood behavior compliance, over a large pool of various biological targets), for any further use the manifolds are ready to provide "fit-free" predictive models...
February 9, 2019: Journal of Computer-aided Molecular Design
Jia Xin Soong, Soo Khim Chan, Theam Soon Lim, Yee Siew Choong
Mycobacterium tuberculosis (Mtb) 16.3 kDa heat shock protein 16.3 (HSP16.3) is a latency-associated antigen that can be targeted for latent tuberculosis (TB) diagnostic and therapeutic development. We have previously developed human VH domain antibodies (dAbs; clone E3 and F1) specific against HSP16.3. In this work, we applied computational methods to optimise and design the antibodies in order to improve the binding affinity with HSP16.3. The VH domain antibodies were first docked to the dimer form of HSP16...
January 28, 2019: Journal of Computer-aided Molecular Design
Xianjin Xu, Zhiwei Ma, Rui Duan, Xiaoqin Zou
Drug Design Data Resource (D3R) continues to release valuable benchmarking datasets to promote improvement and development of computational methods for new drug discovery. We have developed several methods for protein-ligand binding mode prediction during the participation in the D3R challenges. In the present study, these methods were integrated, automated, and systematically tested using the large-scale data from Continuous Evaluation of Ligand Pose Prediction (CELPP) and a subset of Grand challenge 3 (GC3)...
January 28, 2019: Journal of Computer-aided Molecular Design
Vagolu Siva Krishna, Shan Zheng, Estharla Madhu Rekha, Luke W Guddat, Dharmarajan Sriram
Tuberculosis (TB) remains a major threat to human health. This due to the fact that current drug treatments are less than optimal and the increasing occurrence of multi drug-resistant strains of etiological agent, Mycobacterium tuberculosis (Mt). Given the wide-spread significance of this disease, we have undertaken a design and evaluation program to discover new anti-TB drug leads. Here, we focused on ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid biosynthesis pathway...
January 21, 2019: Journal of Computer-aided Molecular Design
Kai Liu, Hironori Kokubo
The fluorination-induced changes in the logP (1-octanol/water partition coefficient) of ligands were examined by molecular dynamics simulations. The protocol and force field parameters were first evaluated by calculating the logP values for n-alkanes, and their monofluorinated and monochlorinated analogs. Then, the logP values of several test sets (1-butanol, 3-propyl-1H-indole, and analogs fluorinated at the terminal methyl group) were calculated. The calculated results agree well with experiment, and the root mean square error values are 0...
January 2, 2019: Journal of Computer-aided Molecular Design
Francesca Spyrakis, Pierangelo Bellio, Antonio Quotadamo, Pasquale Linciano, Paolo Benedetti, Giulia D'Arrigo, Massimo Baroni, Laura Cendron, Giuseppe Celenza, Donatella Tondi
The worldwide spread of beta-lactamases with hydrolytic activity extended to last resort carbapenems is aggravating the antibiotic resistance problem and endangers the successful antimicrobial treatment of clinically relevant pathogens. As recently highlighted by the World Health Organization, new strategies to contain antimicrobial resistance are urgently needed. Class A carbapenemases include members of the KPC, GES and SFC families. These enzymes have the ability to hydrolyse penicillins, cephalosporins and carbapenems, while also being less susceptible to available beta-lactam inhibitors, such as clavulanic acid...
January 2, 2019: Journal of Computer-aided Molecular Design
Lucia Fusani, Alvaro Cortes Cabrera
The COMBINE method was designed to study congeneric series of compounds including structural information of ligand-protein complexes. Although very successful, the method has not received the same level of attention than other alternatives to study Quantitative Structure Active Relationships (QSAR) mainly because lack of ways to measure the uncertainty of the predictions and the need for large datasets. Active learning, a semi-supervised learning approach that makes use of uncertainty to enhance models' performance while reducing the size of the training sets, has been used in this work to address both problems...
December 18, 2018: Journal of Computer-aided Molecular Design
Kostas A Triantaphyllopoulos, Fotis A Baltoumas, Stavros J Hamodrakas
Natural Resistance-Associated Macrophage Proteins are a family of transmembrane divalent metal ion transporters, with important implications in life of both bacteria and mammals. Among them, the Solute Carrier family 11 member A1 (SLC11A1) has been implicated with susceptibility to infection by Mycobacterium avium subspecies paratuberculosis (MAP), potentially causing Crohn's disease in humans and paratuberculosis (PTB) in ruminants. Our previous research had focused on sequencing the mRNA of the caprine slc11a1 gene and pinpointed polymorphisms that contribute to caprine SLC11A1's susceptibility to infection by MAP in PTB...
December 12, 2018: Journal of Computer-aided Molecular Design
A T Hagler
In the previous paper, we reviewed the origins of energy based calculations, and the early science of FF development. The initial efforts spanning the period from roughly the early 1970s to the mid to late 1990s saw the development of methodologies and philosophies of the derivation of FFs. The use of Cartesian coordinates, derivation of the H-bond potential, different functional forms including diagonal quadratic expressions, coupled valence FFs, functional form of combination rules, and out of plane angles, were all investigated in this period...
November 30, 2018: Journal of Computer-aided Molecular Design
Pnina Dauber-Osguthorpe, A T Hagler
In this perspective, we review the theory and methodology of the derivation of force fields (FFs), and their validity, for molecular simulations, from their inception in the second half of the twentieth century to the improved representations at the end of the century. We examine the representations of the physics embodied in various force fields, their accuracy and deficiencies. The early days in the 1950s and 60s saw FFs first introduced to analyze vibrational spectra. The advent of computers was soon followed by the first molecular mechanics machine calculations...
November 30, 2018: Journal of Computer-aided Molecular Design
Wen Hu, Liu Qin, Menglong Li, Xuemei Pu, Yanzhi Guo
Identifying protein-RNA binding residues is essential for understanding the mechanism of protein-RNA interactions. So far, rigid distance thresholds are commonly used to define protein-RNA binding residues. However, after investigating 182 non-redundant protein-RNA complexes, we find that it would be unsuitable for a certain amount of complexes since the distances between proteins and RNAs vary widely. In this work, a novel definition method was proposed based on a flexible distance cutoff. This method can fully consider the individual differences among complexes by setting a variable tolerance limit of protein-RNA interactions, i...
November 26, 2018: Journal of Computer-aided Molecular Design
Stefan A P Lenz, Stacey D Wetmore
Parasitic protozoa rely on nucleoside hydrolases that play key roles in the purine salvage pathway by catalyzing the hydrolytic cleavage of the N-glycosidic bond that connects nucleobases to ribose sugars. Cytidine-uridine nucleoside hydrolase (CU-NH) is generally specific toward pyrimidine nucleosides; however, previous work has shown that replacing two active site residues with Tyr, specifically the Thr223Tyr and Gln227Tyr mutations, allows CU-NH to process inosine. The current study uses molecular dynamics (MD) simulations to gain atomic-level insight into the activity of wild-type and mutant E...
November 26, 2018: Journal of Computer-aided Molecular Design
Zied Gaieb, Conor D Parks, Michael Chiu, Huanwang Yang, Chenghua Shao, W Patrick Walters, Millard H Lambert, Neysa Nevins, Scott D Bembenek, Michael K Ameriks, Tara Mirzadegan, Stephen K Burley, Rommie E Amaro, Michael K Gilson
The Drug Design Data Resource aims to test and advance the state of the art in protein-ligand modeling by holding community-wide blinded, prediction challenges. Here, we report on our third major round, Grand Challenge 3 (GC3). Held 2017-2018, GC3 centered on the protein Cathepsin S and the kinases VEGFR2, JAK2, p38-α, TIE2, and ABL1, and included both pose-prediction and affinity-ranking components. GC3 was structured much like the prior challenges GC2015 and GC2. First, Stage 1 tested pose prediction and affinity ranking methods; then all available crystal structures were released, and Stage 2 tested only affinity rankings, now in the context of the available structures...
January 2019: Journal of Computer-aided Molecular Design
Mikhail Ignatov, Cong Liu, Andrey Alekseenko, Zhuyezi Sun, Dzmitry Padhorny, Sergei Kotelnikov, Andrey Kazennov, Ivan Grebenkin, Yaroslav Kholodov, Istvan Kolosvari, Alberto Perez, Ken Dill, Dima Kozakov
Manifold representations of rotational/translational motion and conformational space of a ligand were previously shown to be effective for local energy optimization. In this paper we report the development of the Monte-Carlo energy minimization approach (MCM), which uses the same manifold representation. The approach was integrated into the docking pipeline developed for the current round of D3R experiment, and according to D3R assessment produced high accuracy poses for Cathepsin S ligands. Additionally, we have shown that (MD) refinement further improves docking quality...
November 12, 2018: Journal of Computer-aided Molecular Design
You-Lin Xue, Qiaoshi Zhang, Yuna Sun, Xiaohong Zhou, Ian P Hurley, Gary W Jones, Youtao Song
Genetics experiments have identified six mutations located in the subdomain IA (A17V, R23H, G32D, G32S, R34K, V372I) of Ssa1 that influence propagation of the yeast [PSI+ ] prion. However, the underlining molecular mechanisms of these mutations are still unclear. The six mutation sites are present in the IA subdomain of the nucleotide-binding domain (NBD). The ATPase subdomain IA is a critical mediator of inter-domain allostery in Hsp70 molecular chaperones, so the mutation and changes in this subdomain may influence the function of the substrate-binding domain...
November 2018: Journal of Computer-aided Molecular Design
Laurence Leherte, Axel Petit, Denis Jacquemin, Daniel P Vercauteren, Adèle D Laurent
The CD2-CD58 protein-protein interaction is known to favor the recognition of antigen presenting cells by T cells. The structural, energetics, and dynamical properties of three known cyclic CD58 ligands, named P6, P7, and RTD-c, are studied through molecular dynamics (MD) simulations and molecular docking calculations. The ligands are built so as to mimic the C and F β-strands of protein CD2, connected via turn inducers. The MD analyses focus on the location of the ligands with respect to the experimental binding site and on the direct and water-mediated hydrogen bonds (H bonds) they form with CD58...
November 2018: Journal of Computer-aided Molecular Design
Gonzalo Cerruela García, Nicolás García-Pedrajas
Feature selection is commonly used as a preprocessing step to machine learning for improving learning performance, lowering computational complexity and facilitating model interpretation. This paper proposes the application of boosting feature selection to improve the classification performance of standard feature selection algorithms evaluated for the prediction of P-gp inhibitors and substrates. Two well-known classification algorithms, decision trees and support vector machines, were used to classify the chemical compounds...
November 2018: Journal of Computer-aided Molecular Design
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