Discovery and development of a new drug is generally known as a very complex process which takes a lot of time and resources. So now a day’s computer aided drug design approaches are used very widely to increase the efficiency of the drug discovery and development course. Various approaches of CADD are evaluated as promising techniques according to their need, in between all these structure-based drug design and ligand-based drug design approaches are known as very efficient and powerful techniques in drug discovery and development. These both methods can be applied with molecular docking to virtual screening for lead identification and optimization. In the recent times computational tools are widely used in pharmaceutical industries and research areas to improve effectiveness and efficacy of drug discovery and development pipeline. In this article we give an overview of computational approaches, which is inventive process of finding novel leads and aid in the process of drug discovery and development research.
Keywords: computer aided drug discovery, structure-based drug design, ligand-based drug design, virtual screening and molecular docking

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Computer aided drug design: an overview

Protein-protein interactions (PPI) are a hallmark of cellular signaling. Such interactions occur abundantly within the cellular milieu and encompass interactions involved in vital cellular processes. Understanding the various types, mechanisms, and consequences of PPIs with respect to cellular signaling and function is vital for targeted drug therapy. Various types of small-molecule drugs and targeted approaches to drug design have been developed to modulate PPIs. Peptidomimetics offer an exciting class of therapeutics as they can be designed to target specific PPIs by mimicking key recognition motifs found at critical points in the interface of PPIs (e.g., hotspots). In contrast to peptides, peptidomimetics do not possess a natural peptide backbone structure but present essential functional groups in a required three-dimensional pattern complimentary to the protein-binding pocket. This design feature overcomes many limitations of peptide therapeutics including limited stability toward peptidases, poor transport across biologic membranes, and poor target specificity. Equally important is deciphering the structural requirements and amino acid residues critical to PPIs. This review provides an up-to-date perspective of the complexity of cellular signaling and strategies for targeting PPIs in disease states, particularly in cancer, using peptidomimetics, and highlights that the rational design of agents that target PPIs is not only feasible but is of the utmost clinical importance.

https://mcr.aacrjournals.org/content/molcanres/12/7/967.full.pdf

Tailoring peptidomimetics for targeting protein-protein interactions

Benzimidazole is a valuable pharmacophore in the field of medicinal chemistry and exhibit wide spectrum of biological activity. Molecular docking technique is routinely used in modern drug discovery for understanding the drug-receptor interaction. The selected data set of synthesized benzimidazole compounds was evaluated for its in vitro anticancer activity against cancer cell lines (HCT116 and MCF7) by sulforhodamine B (SRB) assay. Further, molecular docking study of data set was carried out by Schrodinger-Maestro v11.5 using CDK-8 (PDB code: 5FGK) and ER-alpha (PDB code: 3ERT) as possible target for anticancer activity. Molecular docking results demonstrated that compounds 12, 16, N9, W20 and Z24 displayed good docking score with better interaction within crucial amino acids and corelate to their anticancer results. ADME results indicated that compounds 16, N9 and W20 have significant results within the close agreement of the Lipinski’s rule of five and Qikprop rule within the range and these compounds may be taken as lead molecules for the discovery of new anticancer agents.

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In-silico molecular design of heterocyclic benzimidazole scaffolds as prospective anticancer agents

Steered molecular dynamic (SMD) is a powerful technique able to accelerate rare event sampling in Molecular Dynamics (MD) simulations by applying an external force to a set of chosen atoms. Despite generating nonequilibrium simulations, SMD remains capable of reconstructing equilibrium properties such as the Potential of Mean Force (PMF). Of course, one would like to use all types of force fields (FF) ranging from classical ones to more advanced polarizable models using point induced dipoles and distributed multipoles such as AMOEBA. To enable such studies, the SMD methodology has been implemented in the framework of the massively parallel Tinker-HP software allowing for both long polarizable and non-polarizable MD simulations of large proteins. To validate this new implementation, we first compared the Tinker-HP SMD results to the literature. Tests have been performed on three different benchmark systems: the M–A deca-alanine (112 atoms), the ubiquitin (9737 atoms), and the CD2CD58 complex (97594 atoms)....

https://pubs.acs.org/doi/pdf/10.1021/acs.jctc.1c00405

Massively Parallel Implementation of Steered Molecular Dynamics in Tinker-HP: Comparisons of Polarizable and Non-Polarizable Simulations of Realistic Systems

A novel flavanone derivative inhibits dengue virus fusion and infectivity.

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Protein-Protein and Protein-Ligand Docking

Microfluidics is a growing area of micro and nanofabrication that found broad applications in molecular biology, chemistry, pharmaceutics, synthesis, optics, and informatics, among others. Microfluidics was developed from the interaction between molecular analysis, biodefence, molecular biology, and microelectronics. Some cell fabrication processes and microfluidics experiments could be expensive, then the computational simulation of experiments is useful to establish the appropriate conditions before the fabrication. In this work, we present the microdroplet production using two immiscible liquids (oil and water), their transport, as well as the general procedure of computational fluid dynamic (CFD) simulation. We used time-dependent two-phase microfluidic flow in 2D with a “T” cell geometry with $\pmb{1}\ \mu \mathbf{m}$ of width. In all cases, droplet production can be achieved until a water inlet velocity limit. We observed an inverse relationship between the droplet distance and the inlet velocity. If the distance between droplets decreases, the inlet velocity increases. However, when water inlet velocity increases to reach the Weber number larger enough to overcome interfacial tension, a continuous flow of water is achieved. This occurs when $\mathbf{v}=\mathbf{0.02}\ \mathbf{m}/\mathbf{s}$ of inlet water flux. We do not observe squeezing regime because $\pmb{x}= \pmb{width}_{\pmb{in}}/\pmb{width}_{\pmb{out}} \ll \pmb{1}$ , and then droplets do not obstruct the channel as it grows, neither restricts the flow of continuous phase.

Microdroplet Formation in Microfluidic Channels by Multiphase Flow Simulation

Chitosan is a naturally occurring compound that can be obtained from deacetylated chitin, which is obtained from various sources such as fungi, crustaceans, and insects. Commercially, chitosan is produced from crustaceans. Based on the range of its molecular weight, chitosan can be classified into three different types, namely, high molecular weight chitosan (HMWC, >700 kDa), medium molecular weight chitosan (MMWC, 150–700 kDa), and low molecular weight chitosan (LMWC, less than 150 kDa). Chitosan shows several properties that can be applied in horticultural crops, such as plant root growth enhancer, antimicrobial, antifungal, and antiviral activities. Nevertheless, these properties depend on its molecular weight (MW) and acetylation degree (DD). Therefore, this article seeks to extensively review the properties of chitosan applied in the agricultural sector, classifying them in relation to chitosan’s MW, and its use as a material for sustainable agriculture.

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Chitosan: Properties and Its Application in Agriculture in Context of Molecular Weight

Microfluidics is a research field which allow us control over liquids at micrometric scale. It has several applications such as chemistry, biomedicine and biology, among others. Microfluidics enable the development of systems capable of cell manipulation and very precise chemical reactions with substantial improvements over common or bulk synthesis, let us fabricate nanocarriers with specific characteristics. In fact, the customization of variables is what makes it so versatile. One of the main issues we deal with is the control and injection of small volume fluids inside the microfluidic cell, ranging in some microliters per hour with a controlled and constant velocity. Commercial systems of this kind are expensive but instead they can be replaced by a home-made system. Here we present the design and implementation of a low cost 4-channel microinjection system by using 3D printing, Arduino and LabView. The implemented pumps are capable to deliver a minimum of 70 µl/h and a maximum of 54 ml/h of fluid, are scalable, easy to reproduce and low cost, making available for a wide range of researchers, the time of development is small compared with the acquisition and importation time, from a couple of days against months, with a price in the range of hundreds instead thousands of dollars and with similar characteristics to those commercially available.

Automatization and control of home-made micro injection pumps for a microfluidic system

This work proposes a feasible, reproducible, and low-cost modified method to manufacture chitosan, chitosan/IgG-protein-loaded, and trimethylated chitosan nanoparticles, using microfluidics combined with the microemulsion technique, which differs from the traditional batch process of chitosan-based nanoparticles. The synthesis process consists of generating microreactors of chitosan-based polymer in a poly-dimethylsiloxane ψ-shaped microfluidic device and then crosslinking with sodium tripolyphosphate outside the cell. Transmission electron microscopy demonstrates an improvement in size control and distribution of the solid-shape chitosan nanoparticles (~80 nm) compared to the batch synthesis. Regarding chitosan/IgG-protein-loaded nanoparticles, these presented a core-shell morphology having a diameter of close to 15 nm. Raman and X-ray photoelectron spectroscopies confirmed the ionic crosslinking between the amino groups of chitosan and the phosphate groups of sodium tripolyphosphate in the fabricated samples and the total encapsulation of IgG protein during the fabrication of chitosan/IgG-loaded nanoparticles. Then, an ionic crosslinking and nucleation-diffusion process of chitosan-sodium tripolyphosphate was carried out during the nanoparticle formation, with and without IgG protein loading. The use of N-trimethyl chloride chitosan nanoparticles in vitro on human-keratinocyte-derived cell line HaCaT did not show side effects independently of its concentration from 1 to 10 μg/mL. Therefore, the proposed materials could be used as potential carrier-delivery systems.

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Aldo Yair Tenorio-Barajas

Papers

Protein-Protein and Protein-Ligand Docking

Microdroplet Formation in Microfluidic Channels by Multiphase Flow Simulation

Chitosan: Properties and Its Application in Agriculture in Context of Molecular Weight

Automatization and control of home-made micro injection pumps for a microfluidic system

Chitosan, Chitosan/IgG-Loaded, and N-Trimethyl Chitosan Chloride Nanoparticles as Potential Adjuvant and Carrier-Delivery Systems