In the past, metal-based compounds were widely used in the treatment of disease conditions, but the lack of clear distinction between the therapeutic and toxic doses was a major challenge. With the discovery of cisplatin by Barnett Rosenberg in 1960, a milestone in the history of metal-based compounds used in the treatment of cancers was witnessed. This forms the foundation for the modern era of the metal-based anticancer drugs. Platinum drugs, such as cisplatin, carboplatin and oxaliplatin, are the mainstay of the metal-based compounds in the treatment of cancer, but the delay in the therapeutic accomplishment of other metal-based compounds hampered the progress of research in this field. Recently, however, there has been an upsurge of activities relying on the structural information, aimed at improving and developing other forms of metal-based compounds and nonclassical platinum complexes whose mechanism of action is distinct from known drugs such as cisplatin. In line with this, many more metal-based compounds have been synthesized by redesigning the existing chemical structure through ligand substitution or building the entire new compound with enhanced safety and cytotoxic profile. However, because of increased emphasis on the clinical relevance of metal-based complexes, a few of these drugs are currently on clinical trial and many more are awaiting ethical approval to join the trial. In this review, we seek to give an overview of previous reviews on the cytotoxic effect of metal-based complexes while focusing more on newly designed metal-based complexes and their cytotoxic effect on the cancer cell lines, as well as on new approach to metal-based drug design and molecular target in cancer therapy. We are optimistic that the concept of selective targeting remains the hope of the future in developing therapeutics that would selectively target cancer cells and leave healthy cells unharmed.

The present art of drug discovery and design of new drugs is based on suicidal irreversible inhibitors. Covalent inhibition is the strategy that is used to achieve irreversible inhibition. Irreversible inhibitors interact with their targets in a time-dependent fashion, and the reaction proceeds to completion rather than to equilibrium. Covalent inhibitors possessed some significant advantages over non-covalent inhibitors such as covalent warheads can target rare, non-conserved residue of a particular target protein and thus led to development of highly selective inhibitors, covalent inhibitors can be effective in targeting proteins with shallow binding cleavage which will led to development of novel inhibitors with increased potency than non-covalent inhibitors. Several computational approaches have been developed to simulate covalent interactions; however, this is still a challenging area to explore. Covalent molecular docking has been recently implemented in the computer-aided drug design workflows to describe covalent interactions between inhibitors and biological targets. In this review we highlight: (i) covalent interactions in biomolecular systems; (ii) the mathematical framework of covalent molecular docking; (iii) implementation of covalent docking protocol in drug design workflows; (iv) applications covalent docking: case studies and (v) shortcomings and future perspectives of covalent docking. To the best of our knowledge; this review is the first account that highlights different aspects of covalent docking with its merits and pitfalls. We believe that the method and applications highlighted in this study will help future efforts towards the design of irreversible inhibitors.

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Herein, for the first time, we report the flap opening and closing in Plasmepsin proteases - plasmepsin II (PlmII) was used as a prototype model. We proposed different combined parameters to define the asymmetric flap motion; the distance, d1, between the flap tip residues (Val78 and Leu292); the dihedral angle, ϕ; in addition to TriCα angles Val78-Asp34-Leu292, θ1, and Val78-Asp214-Leu292, θ2. Only three combined parameters, the distance, d1, the dihedral angle, ϕ, and the TriCα angle, θ1, were found to appropriately define the observed "twisting' motion during the flap opening and closing. The coordinated motions of the proline-rich loop adjacent to the binding cavity rim appeared to exert steric hindrance on the flap residues, driving the flap away from the active site cavity. This loop may also have increased movements around the catalytic dyad residue, Asp214, making TriCα, θ2, unreliable in describing the flap motion. The full flap opening at d1, 23.6 Å, corresponded to the largest TriCα angle, θ1, at 78.6° on a ∼46 ns time scale. Overall the average θ1 and θ2 for the bound was ∼46° and ∼53°, respectively, compared to ∼50° and ∼59° for the Apo PlmII, indicating a drastic increase in TriCα as the active site cavity opens. Similar trends in the distance, d1, and the dihedral angle, ϕ, were observed during the simulation. The asymmetrical opening of the binding cavity was best described by the large shift in ϕ from -33.91° to +21.00° corresponding to the partial opening of the flap in the range of 22-31 ns. Though, the dihedral angle described the twisting of the flap, the extent of flap opening can appropriately be defined by combining d1 and θ1. The results presented here, on the combined parameters, will certainly augment current efforts in designing potent structure-based inhibitors against plasmepsins.

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The emergence of different drug resistant strains of HIV-1 reverse transcriptase (HIV RT) remains of prime interest in relation to viral pathogenesis as well as drug development. Amongst those mutations, M184V was found to cause a complete loss of ligand fitness. In this study, we report the first account of the molecular impact of M184V mutation on HIV RT resistance to 3TC (lamivudine) using an integrated computational approach. This involved molecular dynamics simulation, binding free energy analysis, principle component analysis (PCA) and residue interaction networks (RINs). Results clearly confirmed that M184V mutation leads to steric conflict between 3TC and the beta branched side chain of valine, decreases the ligand (3TC) binding affinity by ∼7 kcal mol(-1) when compared to the wild type, changes the overall conformational landscape of the protein and distorts the native enzyme residue-residue interaction network. The comprehensive molecular insight gained from this study should be of great importance in understanding drug resistance against HIV RT as well as assisting in the design of novel reverse transcriptase inhibitors with high ligand efficacy on resistant strains.

We report the first account of a comparative analysis of the binding affinities of nine FDA-approved drugs against subtype B as well as the South African subtype C HIV PR (C-SA). A standardized protocol was used to generate the inhibitor/C-SA PR complexes with the relative positions of the inhibitors taken from the corresponding X-ray structures for subtype B complexes. The dynamics and stability of these complexes were investigated using molecular dynamics calculations. Average relative binding free energies for these inhibitors were calculated from the molecular dynamics simulation using the molecular mechanics generalized Born surface area method. The calculated energies followed a similar trend to the reported experimental binding free energies. Postdynamic hydrogen bonding and electrostatic interaction analysis of the inhibitors with both subtypes reveal similar interactions. Most inhibitors show slightly weaker binding affinities for C-SA PR. Molecular dynamics studies demonstrated increased flap movement for C-SA PR, which can perhaps explain the weaker affinities. This study serves as a standardized platform for optimizing the design of future more potent HIV C-SA PR inhibitors.

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