Design of novel ROCK inhibitors using fragment-based de novo drug design approach
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ORIGINAL PAPER
Design of novel ROCK inhibitors using fragment-based de novo drug design approach Hemant Arya 1 & Mohane Selvaraj Coumar 1 Received: 27 March 2020 / Accepted: 30 July 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Rho-associated coiled-coil protein kinase (ROCK) is playing a vital role in the regulation of key cellular events and also responsible for causing several pathological conditions such as cancer, hypertension, Alzheimer’s, cerebral vasospasm, and cardiac stroke. Therefore, it has attracted us to target ROCK protein as a potential therapeutic target for combating various diseases. Consequently, we investigated the active site of ROCK I protein and designed novel leads against the target using the de novo evolution drug design approach. Caffeic acid (an aglycone of acteoside) as a scaffold and fragments from 336 reported ROCK inhibitors were used for the design of novel leads. Multiple copy simultaneous search docking was used to identify the suitable fragments to be linked with the scaffold. Basic medicinal chemistry rules, coupled with structural insights generated by docking, led to the design of 7a, 8a, 9a, and 10a as potential ROCK I inhibitors. The designed leads showed better binding than the approved drug fasudil and also interacted with the key hinge region residue Met156 of ROCK I. Further, molecular dynamics (MD) simulation revealed that the protein-ligand complexes were stable and maintained the hydrogen bond with Met156 throughout the MD run. The promising in silico outcomes suggest that the designed compounds could be suitable anti-cancer leads that need to be synthesized and tested in various cancer cell lines. Keywords Caffeic acid . De novo drug design . Ludi algorithm . MCSS docking . Molecular dynamics . ROCK inhibitor
Introduction Computer-aided drug design (CADD) is a modern computational technique used in the drug discovery process to identify and develop a potential lead. CADD techniques are gaining popularity and appreciation both in academic circles and in pharmaceutical industries, as it saves time and is also costeffective in discovering drugs. CADD approach can be utilized in four different contexts within a drug discovery programs: (1) to screen small molecule library using virtual screening (VS) protocol to identify hits/leads, (2) to investigate specificity of the selected hits for a particular target using molecular docking, (3) for predicting ADMET properties of Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00894-020-04493-3) contains supplementary material, which is available to authorized users. * Mohane Selvaraj Coumar [email protected] 1
Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry 605014, India
the selected hits, and (4) to optimize the hits activity/property using structure-based drug design approach. Several techniques/strategies, such as molecular docking, virtual screening, fragment-based method, de novo approach, pharm
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